Cristen D LaPierre¹, Mathieu Sarracanie^1,2, Brandon Dean Armstrong^1,2, Jonathan R Polimeni^1,3, and Matthew S Rosen^1,2
1Department of Radiology, A.A. Martinos Center for Biomedical Imaging, Charlestown, MA, United States, ²Department of Physics, Harvard University, Cambridge, MA, United States, ³Harvard Medical School, Boston, MA, United States

Low SNR and long acquisition times are the primary hindrance to deployable low-field MRI scanners. .Due to low Boltzmann polarization, enhancement techniques such as Dynamic Nuclear Polarization (DNP) and image acceleration techniques like SENSitivity Encoding (SENSE) will be vital to obtaining high quality images in reasonable times. In this study an eight-coil receive-only array for 6.5 mT was used with a 14 cm saddle coil and 30 cm NMR Transmit coil to acquire DNP + SENSE images of a structured phantom. Future work will improve SENSE reconstruction as well as compare it to incoherent random undersampling strategies.

Markus Durst^1,2, Ulrich Koellisch^1,2, Francesca Reineri³, Valeria Daniele³, Concetta Gringeri⁴, Annette Frank⁴, Marion I. Menzel², Axel Haase¹, Rolf F. Schulte², and Silvio Aime^3
1IMETUM, Technische Universität München, Garching, Germany, ²GE Global Research, Garching, Germany, ³Department Chemistry I.F.M. and Molecular Imaging Center, University of Torino, Torino, Italy, ⁴Klinikum rechts der Isar, Technische Universität München, München, Germany

Dynamic nuclear polarisation has enabled the analysis of metabolic pathways in real-time using hyperpolarised substrates. The conversion of [1-13C]pyruvate to downstream metabolites such as lactate and alanine can provide an important tool for studying diseases with abnormal cellular metabolism such as cancer or ischemia. In this work, an extracellular relaxation agent (GdDO3A) was used to quasi-instantaneously quench the extracellular compartment of the metabolites. In combination with a substrate saturation sequence, transporter rates for the cell membrane transport of hyperpolarised metabolites could be quantified for the first time in vivo.

Marc S Ramirez¹, Jaehyuk Lee¹, Avinashnarayan Venkatanarayan², Elsa R Flores², and James A Bankson^1
1Department of Imaging Physics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States, ²Department of Biochemistry and Molecular Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States

In this work, we evaluate the initial feasibility of detecting elevated aerobic glycolysis in a spontaneous transgenic mouse model of thymic lymphoma, which is challenging due to the close proximity of the thymus to the heart, where high levels of pyruvate and its metabolites could confound data analysis. Dynamic MRS using hyperpolarized [1-¹³C] pyruvate was performed on p53-/- mice at various stages of disease progression. High correlation between tumor volume and normalized lactate confirms that hyperpolarized measurements are indeed modulated by tumor metabolism, establishing the initial feasibility for metabolic investigations in a spontaneous transgenic model of lymphoma.

Emine Can¹, Mor Mishkovsky^2,3, Rolf Gruetter^2,4, and Arnaud Comment^1
1Institute of Physics of Biological Systems, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, ²Laboratory for Functional and Metabolic Imaging (LIFMET), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, ³Department of radiology, University of Lausanne, Lausanne, Switzerland, ⁴Department of radiology, University of Lausanne and Geneva, Switzerland

The present study demonstrates the use of the hydrophobic radical 2,2-Diphenyl-1-picrylhydrazyl (DPPH) to polarize acidic metaboilc precursors such as acetic acid (AcOH) and pyruvic acid (PA). Additional, we describe a complete atumated protocol that includes rapid dissolution and transfer, filtration and infusion of radical free solution to an animal. Polarization efficiency is quantified and the aplicablitiy to in vivo ¹³C MRS study of hyperpolarized AcOH and PA metabolism is presented.

Shuyu Tang¹, Hsin-Yu Chen¹, Robert A. Bok¹, Daniel B. Vigneron¹, and Peder Larson^1
1Department of Radiology and Biomedical Imaging, UCSF, San Francisco, California, United States

Hyperpolarization of metabolically active compounds labeled with ¹³C is an emerging approach for imaging metabolic processes in vivo. We designed a new two-dimensional spatially-selective radiofrequency (2DRF) pulse for bolus tracking in hyperpolarized ¹³C imaging. Advantages of applying 2DRF in hyperpolarized ¹³C imaging include reducing polarization loss and shortening acquisition time. Due to the use of a spiral excitation trajectory, our design allows for minimal perturbation of other off-resonance metabolites. Since our 2DRF pulse was developed for a 3T clinical scanner with conventional gradient performances, rapid translation of our design to human studies is possible.

Wenwen Jiang^1,2, Michael Lustig³, Martin Uecker³, and Peder E.Z. Larson^4
1Graduate Group in Bioengineering, University of California, Berkeley, Berkeley, California, United States, ²University of California, San Francisco, San Francisco, California, United States, ³Electrical Enigneering and Computer Science, University of California, Berkeley, California, United States, ⁴Radiology and Biomedical Imaging, University of California, San Francisco, California, United States

The short-lived effect of hyperpolarization of ¹³C poses severe challenges to develop rapid and robust imaging techniques. The concentric rings trajectory is such a technique for ¹³C spectroscopic imaging because 1) it is as twice efficient as Cartesian trajectory; 2) it exhibits robustness to minor system imperfections; 3) it retains the ability of variable density and good parallel imaging properties; 4) and it is insusceptible to pulsatile flow artifacts. Preclinical studies have been performed for evaluation. Concentric rings trajectory shows great potential to be applied for accelerated hyperpolarized ¹³C MRSI.

Shingo Matsumoto¹, Keita Saito¹, Jeeva P Munasinghe², Herman D Morris², Martin J Lizak², Shun Kishimoto¹, Nallathamby Devasahayam¹, Sankaran Suburamanian¹, James B Mitchell¹, and Murali C Krishna^1
1National Cancer Institute, NIH, Bethesda, MD, United States, ²National Institute of Neurological Disorder and Stroke, Bethesda, MD, United States

Anti-angiogenic therapies of solid tumors frequently proceed in two steps: transient normalization of structurally and functionally aberrant tumor blood vessels with increased blood perfusion, followed by pruning the tumor blood vessels and resultant cessation of nutrients and oxygen delivery required for tumor growth. We investigated if imaging of redox status governed by redox sensitive metabolic couples in tumors can serve as non-invasive surrogate makers for the vascular normalization window. Multimodal imaging approach of tumor physiological, metabolic and redox changes is useful to distinguish different stages in the course of anti-angiogenic treatment.

Rajat K. Ghosh¹, Stephen J. Kadlecek¹, Mehrdad Pourfathi¹, and Rahim R. Rizi^1
1University of Pennsylvania, Philadelphia, PA, United States

Synopsis: Several medical conditions such as acute lung injury, cancer, ischemia, and inflammation result in alterations to the acid-base balance in tissue. Hyperpolarized bicarbonate has been able to determine the pH in-vivo. However the highest polarization of bicarbonate is achieved using cesium salts. This is not translatable to a clinical setting, as cesium ions are highly toxic. We generate hyperpolarized bicarbonate by decarboxylating the hyperpolarized pyruvate. This leads to a high polarization without the use of cesium, and allows for increased imaging resolution. We demonstrate imaging with 1.2mmx1.2mm in plane resolution, which could be increased to 0.5mmx0.5mm.

Damian J Tyler¹, Angus Z Lau^1,2, and Daniel R Ball^1
1Dept. of Physiology, Anatomy & Genetics, University of Oxford, Oxford, Oxfordshire, United Kingdom, ²Dept. of Cardiovascular Medicine, University of Oxford, Oxford, Oxfordshire, United Kingdom

Hyperpolarization of [1-¹³C]pyruvate provides a unique insight into various aspects of carbohydrate metabolism. However, alterations in the metabolic pathways of other key fuel molecules (e.g. fatty acids and ketone bodies) are a common feature of many diseases. This work aimed to produce a reliable method to hyperpolarize the ketone bodies, acetoacetate and β-hydroxybutyrate, and to investigate their metabolism in the perfused rat heart. Following successful polarization of both substrates, perfusion into the isolated rat heart enabled direct visualization of the interconversion between the ketone bodies along with observation of their downstream metabolism in the Krebs cycle.

Kamil Lorenc¹, Eugen Kubala^2,3, Concetta V. Gringeri^2,4, Markus Durst^4,5, Ulrich Koellisch^4,5, Annette Frank², Markus Schwaiger², Steffen J. Glaser³, Rolf F. Schulte⁴, and Marion I. Menzel^4
1Nalecz Institute of Biocybernetics and Biomedical Engineering, PAS, Warsaw, Poland, ²Klinikum rechts der Isar, TU München, Munich, Germany, ³Department of Chemistry, TU München, Munich, Germany, ⁴GE Global Research, Munich, Germany, ⁵Institute of Medical Engineering, TU München, Munich, Germany

Recently, there is growing evidence that D-fructose plays a role in neuroenergetics. Depending on tissue D-fructose is metabolized through Fructose-1-phosphate, or Fructose-6-phosphate metabolic pathway, however, in brain Fructose-6-phosphate metabolic pathway is used exclusively. The aim was to find out if hyperpolarized [2-¹³C]-D-fructose is able to cross blood brain barrier in sufficient amount enabling the measurement using 13CMMR. We observed a very clear signal in all of the measurements, meaning that D-fructose was able to cross blood brain barrier in sufficient amount. In future D-fructose is a good candidate for functional imaging studies, and due to non-toxicity it may be applied in human.

Naeim Bahrami¹, Christine Leon¹, Cornelius Von Morze¹, Daniel B. Vigneron¹, and Peder E.Z. Larson^1
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, United States

The primary purpose of this research was to model the kinetics of hyperpolarized (HP) pyruvate and urea to provide improved characterization of cancerous tissues when using arbitrary RF flip angles in dynamic MRSI. This modeling has the ability to detect metabolic conversion and perfusion. The conversion constant of metabolites will increase in tumor with respect to healthy tissues. In this study, we measured T1 values of metabolites including pyruvate, urea, alanine, and lactate in tumor and healthy tissues.

Stephan Düwel^1,2, Patrick Christ^1,3, Ulrich Köllisch^1,3, Markus Durst^1,3, Concetta V Gringeri^3,4, Franz Schilling⁴, Marion I Menzel³, Rolf F Schulte³, Steffen Glaser², Markus Schwaiger⁴, and Axel Haase^1
1Institute of Medical Engineering, Technische Universität München, Garching, Germany, ²Department of Chemistry, Technische Universität München, Garching, Germany, ³GE Global Research, Garching, Germany, ⁴Institute of Nuclear Medicine, Klinikum Rechts der Isar, Munich, Germany

Through hyperpolarized ¹³C MRSI, the labeled compounds pyruvate, alanine, lactate, urea and acetate allow real-time in-vivo studies of energy metabolism, perfusion and short chain fatty acid metabolism, respectively. In hyperpolarized experiments, the signal-to-noise-ratio is independent of the magnetic field strength B₀, but spectral resolution and spin-lattice relaxation times T₁ can strongly depend on B₀. We measured T₁ for the five aforementioned compounds at clinically available field strengths (1T, 3T, 7T) and 14T with constant pH and temperature in a buffer solution. Within the statistical uncertainty, T₁ decreases with increasing B₀ for all substances, but the degree depends on the compound.

Young-suk Choi¹, Joon-Sung Lee^2,3, Han-Sol Lee³, Hyun-Jin Park¹, Ju-Hyun Lee¹, Eun-Kyung Wang¹, Seung-Wook Yang³, Eun-Hae Joe³, Dong-Hyun Kim³, and Ho-Taek Song^1
1Department of Radiology, Yonsei University College of Medicine, Seodaemun-Gu, Seoul, Korea, ²SIRIC, Yonsei University College of Medicine, Seodaemun-Gu, Seoul, Korea,³Department of Eletrical & Electronic Engineering, Yonsei University, Seodaemun-Gu, Seoul, Korea

In brain metastasis from breast cancer mouse model, we evaluate the pyruvate to lactate conversion ratio to monitor the alteration of metabolism by metformin by hyperpolarized 13C metabolic MRS imaging. The inhibition of tumor growth by metformin was not proved by conventional imaging and hyperpolarized 13C MRSI. Individual conversion ratio of 13C pyruvate to 13C lactate showed inverse correlation with survival regardless of experimental group. Hyperpolarized 13C MRSI may be useful tool to predict the prognosis cancer patients.

Concetta Valeria Gringeri^1,2, Eugen Kubala^1,2, Ulrich Koellisch^2,3, Annette FranK¹, Rolf Schulte², Axel Haase³, Markus Schwaiger¹, Steffen Glaser⁴, and Marion Irene Menzel^2
1Institute of Nuclear Medicine, Klinikum rechts der Isar, TUM, Munich, Bayern, Germany, ²GE Global Research, Munich, Bayern, Germany, ³IMETUM, TUM, Munich, Bayern, Germany, ⁴Department of Chemistry, TUM, Munich, Bayern, Germany

A change in neurotransmitter levels (glutamate, glutamine and GABA) was demonstrated recently in the striatum at Parkinson’s disease models using 1H MRS. Glutamine is able to cross the BBB by facilitated diffusion, however compared to other neutral amino acids this process is slower. Therefore brain distribution of hyperpolarized [5-13C]-glutamine was imaged in Lewis healthy rats. A sufficient glutamine signal was detected in different brain areas. In the main future 13C-MRI might provide novel and more selective tools to study the transport systems and evaluate their regulation in vivo. In this sense hyperpolarized glutamine can be considered a promising candidate.

Stephen J. Kadlecek¹, Hoora Shaghaghi¹, Mehrdad Pourfathi¹, Sarmad Siddiqui¹, Jennia Rajaei¹, Profka Harrilla¹, and Rahim R. Rizi^1
1Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States

We present the measurements of lactate pool labeling rates in the isolated, perfused rat lung using hyperpolarized 1-13C pyruvate. The rates are shown to vary strongly with perfusate constituents (unpolarized lactate and pyruvate, as well as hyperpolarized pyruvate concentration and can be accurately reproduced using a three-compartment model which incorporates previously measured transport and enzymatic activity measurements, as well as concentrations of enzyme and cofactors. We conclude that intracellular conditions (e.g., redox state) are strongly perturbed during a typical hyperpolarized pyruvate measurement, and that consideration of metabolic flux through LDH is not necessary to reproduce experimental results.

Kasper Wigh Lipsø^1,2, Peter Magnusson¹, Lise Vejby Søgaard¹, and Jan Henrik Ardenkjær-Larsen^2,3
1Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark, ²Department of Electrical Engineering, Technical University of Denmark, Kgs. Lyngby, Denmark, ³GE Healthcare, Brøndby, Denmark

We compare non-contrast enhanced MRA, SPIO enhanced MRA and hyperpolarized ¹³C MRA in rat cerebral regions, and demonstrate how venous structures can be imaged with acquisition times less than a second. We describe optimized sequence designs for each of the techniques. The hyperpolarized ¹³C shows promising results for angiographic imaging where short acquisition time is essential, such as imaging within a single heartbeat or breath hold.

Najat Salameh¹, Jean-Noël Hyacinthe², Andrea Capozzi¹, and Arnaud Comment^1
1Institut de Physique des Systèmes Biologiques, École Polytechnique Fédérale de Lausanne, Lausanne, Lausanne, Switzerland, ²Haute École de Santé, University of Applied Sciences Western Switzerland, Geneva, Switzerland

Aaron M. Coffey^1,2, Roman V. Shchepin², Danila A. Barskiy^3,4, Kirill V. Kovtunov^3,4, Igor V. Koptyug^3,4, Kevin W. Waddell^2,5, Ping He⁶, Kirsten A. Groome⁶, Quinn A. Best⁶, Fan Shi⁶, Boyd M. Goodson⁶, and Eduard Y. Chekmenev^1,2
1Biomedical Engineering, Vanderbilt University, Nashville, TN, United States, ²Radiology, Vanderbilt University Institute of Imaging Science, Nashville, TN, United States,³International Tomography Center, Novosibirsk, 630090, Russian Federation, ⁴Novosibirsk State University, Novosibirsk, 630090, Russian Federation, ⁵Physics, Vanderbilt University, Nashville, TN, United States, ⁶Chemistry and Biochemistry, Southern Illinois University, Carbondale, IL, United States

Nuclear spin polarization P is a key factor for MRI sensitivity, with various hyperpolarization techniques permitting orders of magnitude increases beyond that afforded by static magnetic fields. Low-field, resonance frequency optimized rf coils can allow imaging of such polarization with greater sensitivity than at high field. High-resolution 0.0475 T proton and ¹³C 2D GRE imaging is demonstrated for pyridine and ¹³C-succinate hyperpolarized via SABRE and PHIP respectively in a 5.75 mT parahydrogen polarizer. Proton in-plane resolution was 94 μm for P ~ 0.5%, and ¹³C in-plane resolution was 250 μm with P ~ 13%.

Tangi Roussel¹, Avigdor Leftin¹, and Lucio Frydman^1
1Department of Chemical Physics, Weizmann Institute of Science, Rehovot, Israel

MR spectroscopic imaging of hyperpolarized 13C1-pyruvate is a promising technique for in vivo mapping of metabolic information. This method is based on dynamic nuclear polarization (DNP) and on a rapid dissolution process to produce a highly polarized metabolic contrast agent. After injection, 13C1-pyruvate and its metabolic products 13C1-lactate, 13C1-alanine and 13C1-bicarbonate can be mapped using a Chemical Shift Imaging (CSI) sequence. In this study, a Variable Flip Angle (VFA) Centric Phase Encoding (CPE) CSI sequence was implemented and applied on hyperpolarized 13C1-pyruvate for imaging the metabolism of mice skeletal muscles during functional stimulations mimicking exercise.

Markus Plaumann¹, Thomas Trantzschel¹, Denise Lego², Claudia Köhn¹, Grit Sauer³, Torsten Gutmann³, Joachim Bargon⁴, Gerd Buntkowsky³, Ute Bommerich², and Johannes Bernarding^1
1Department for Biometrics und Medical Informatics, Otto-von-Guericke-University Magdeburg, Magdeburg, Saxony-Anhalt, Germany, ²Special Lab Non-Invasive Brain Imaging, Leibniz Institute for Neurobiology, Magdeburg, Saxony-Anhalt, Germany, ³Institute for Physical Chemistry, Technical University Darmstadt, Darmstadt, Hesse, Germany,⁴Institute of Physical and Theoretical Chemistry, University Bonn, Bonn, North Rhine-Westphalia, Germany

Amino acids are highly relevant in biological pathways and for protein and enzyme structures or for the synthesis of neurotransmitter. An essential amino acid is L-phenylalanine (Phe). The use of fluorinated amino acids are of great interest in medical chemistry and diagnostics especially for the investigation of amino acid metabolism, protein structures and protein-ligand interactions. The disadvantage of low spin density in vivo can be overcome by hyperpolarization methods like Parahydrogen Induced Polarization. We present the hyperpolarization of a bisfluorinated phenylalanine derivative and studies of the interaction between Phe and -cyclodextrin.

Thomas Trantzschel¹, Denise Lego², Markus Plaumann¹, Grit Sauer³, Torsten Gutmann³, Joachim Bargon⁴, Gerd Buntkowsky³, Johannes Bernarding¹, and Ute Bommerich^2
1Department for Biometry and Medical Informatics, Otto-von-Guericke Univerität Magdeburg, Magdeburg, Germany, ²Leibniz Institute for Neurobiology, Magdeburg, Germany,³Eduard-Zintl-Institute for Inorganic Chemistry, Technical University Darmstadt, Darmstadt, Germany, ⁴Institute of Physical and Theoretical Chemistry, Bonn, Germany

Parahydrogen Induced Polarization (PHIP) is increasingly used as a promising tool for medical/biological applications in magnetic resonance as it can increase MR-sensitivity by orders of magnitude. So far only a few number of molecules acting as metabolic sensors were already hyperpolarized with PHIP, but the direct hyperpolarization of drugs used in the treatment of neurological disorders was not achieved so far. In this study the feasibility of applying PHIP to valproate (used in epilepsy treatment) and structurally related molecules with different side chains was examined in NMR and MRI experiments.

Trevor P. Wade^1,2, Lanette Friesen-Waldner², Curtis N. Wiens³, Kevin J. Sinclair², Rachel Katz-Brull^4,5, and Charles A. McKenzie^1,2
1Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada, ²Medical Biophysics, The University of Western Ontario, London, Ontario, Canada,³Radiology, University of Wisconsin, Madison, WI, United States, ⁴Radiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, ⁵BrainWatch Ltd., Tel-Aviv, Israel

Choline is important in cellular membrane construction, so there is interest in developing an MRI choline molecular probe. This study determined if uptake of hyperpolarized [1,1,2,2-D₄, 1-¹³C]-Choline (CMP1) in rat kidneys is due to a saturable cellular transport process or an extracellular diffusion process. Dynamic, 1D images of rat kidneys were obtained after injection of four different doses of CMP1. If CMP1 uptake in kidneys was due solely to diffusion, the kidney signal would increase linearly with concentration. Instead, it began to plateau. This implies a saturable transport process occurs, and uptake is not limited to diffusion.

Christopher M Walker¹, Mark S Ramirez¹, Jaehyuk Lee¹, and James A Bankson^1
1Imaging Physics, M.D. Anderson, Houston, Texas, United States

One barrier to efficient development and validation of advanced imaging techniques for hyperpolarized agents is then current lack of a practical model for the complex biology probed by hyperpolarized MR. To fill this need we propose a multi compartment single enzyme phantom that allows repeatable conversion of pyruvate to lactate in a tunable manner for mimicking different tissue states. We have demonstrated the phantoms spatial dependence with both multichannel spectral measurements and cumulative spectral Imaging. This platform has the potential to speed development and implementation of complex imaging strategies for efficient hyperpolarized MR.

Claudia Köhn¹, Thomas Trantzschel¹, Markus Plaumann¹, Ute Bommerich², Denise Lego², and Johannes Bernarding^1
1Biometrics und Medical Informatics, Otto-von-Guericke-University Magdeburg, Magdeburg, Sachsony-Anhalt, Germany, ²Special Lab Non-Invasive Brain Imaging, Leibniz Institute for Neurobiology, Magdeburg, Sachsony-Anhalt, Germany

To increase the SNR in earth's magnetic field NMR the macroscopic spin order of parahydrogen can be used to produce hyperpolarization. Therefore after an unsaturated substrate is hydrogenated with parahydrogen field cycling has to be applied. Here, we show that a preparation field in the regime of mT switched on for several seconds enables the transfer of PHIP-generated hyperpolarization from parahydrogen to ¹⁹F and that this process is field dependent. For the measurement a self built coil based earth field spectrometer was used.

Karlos X Moreno¹, Eunsook Jin¹, Jian-Xiong Wang¹, A Dean Sherry¹, Matthew E Merritt¹, and Craig R Malloy^1
1Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, United States

In vivo hepatic metabolism of hyperpolarized [1-13C]pyruvate is not known to produce 13C-enriched blood glucose. Rats were either infused simultaneously with [3-13C]pyruvate and [U-13C]octanoate or saline before injection with hyperpolarized [1-13C]pyruvate Hyperpolarized [13C]bicarbonate was observed in several animals. Carbon-13 isotopomer analysis of purified blood glucose showed a large amount of 13C enrichment from pyruvate/octanoate infused animals. Saline infused animals showed a small amount of 13C-enrichment. Also evident were spin-spin 13C couplings was observed as being derived from two molecules of [1-13C]pyruvate forming one molecule of glucose. Integration of hyperpolarized and conventional 13C-NMR is a powerful method for monitoring liver metabolism.

Seungwook Yang¹, Joonsung Lee^2,3, Eunhae Joe¹, Hansol Lee¹, Young-Suk Choi⁴, Ho-Taek Song⁴, and Dong-Hyun Kim^1
1Department of Electrical and Electronic Engineering, Yonsei University, Seoul, Korea, ²Nano-Medical National Core Research Center, Yonsei University, Seoul, Korea, ³SIRIC, Yonsei, Seoul, Korea, ⁴Department of Radiology, College of Medicine, Yonsei University, Seoul, Korea

A method for frequency-selective, high-resolution acquisition of hyperpolarized substrate and its downstream metabolites in vivo in 9.4T is presented. The spatial displacement caused by the chemical shift is utilized in the acquisition of metabolite-selective images by modifying the slice-selection gradients’ duration and polarity. By doing so, spectral bands of neighboring resonances can be pushed outside the subject while acquisition is done in a frequency-interleaved manner. In this work, a simple implementation of this concept into a conventional 3D CSI sequence is presented, along with initial application results from in vivo mouse kidney experiment in 9.4T.

Sami Jannin^1,2, Aurélien Bornet¹, Jonas Milani¹, Basile Vuichoud¹, Roberto Melzi³, Angel J. Perez Linde¹, Patrick Hautle⁴, Ben van den Brandt⁴, Joost Lohman⁵, and Geoffrey Bodenhausen^1,6
1EPFL, Lausanne, Vaud, Switzerland, ²Bruker BioSpin AG, Fallanden, Zurich, Switzerland, ³Bruker Italia, Milano, Italy, ⁴PSI, Villigen, Switzerland, ⁵Bruker UK Limited, Coventry, United Kingdom, ⁶Département de Chimie, ENS, Paris, France

We show an efficient route for rapidly generating 13C hyperpolarization on molecules such as pyruvate at polarization levels exceeding P(13C)>40% in less than 30 minutes. The method begins by the rapid and efficient hyperpolarization of 1H spins (P(1H)>80% in less than 5 minutes) at low temperature and high field (T = 1.2 K and B0 = 6.7 T) using the inexpensive polarizing agent TEMPOL, in combination with rapid 1H→13C polarization transfer by cross-polarization (CP) at low temperature in typically less than 2 ms.

Roberta M Strigel¹, Erin Adamson², David J Niles², Amy Rapaich Moser^3,4, Jeremy W Gordon², Elizabeth S Burnside^1,4, and Sean B Fain^1,2
1Radiology, University of Wisconsin, Madison, WI, United States, ²Medical Physics, University of Wisconsin, Madison, WI, United States, ³Human Oncology, University of Wisconsin, Madison, WI, United States, ⁴Carbone Cancer Center, University of Wisconsin, Madison, WI, United States

Hyperpolarized(HP) carbon-13(¹³C) MR spectroscopic imaging was performed to detect the metabolic features of tumorigenesis in a mouse model of mammary malignancy. 11 mice with tumors were imaged on a 4.7T small animal MR system. Dynamic ¹³C imaging was performed after intravenous (IV) injection of HP ¹³C-pyruvate followed by dynamic contrast enhanced (DCE) MRI using IV gadodiamide. Lactate was identified as a metabolite of HP ¹³C-pyruvate in 2/11 mice. Preliminary results demonstrate inconsistency between contrast-enhanced perfusion and HP ¹³C-lactate, suggesting that HP ¹³C imaging may identify spatial heterogeneity in metabolism, within and between tumors, which differs from perfusion with DCE MRI.

Hoora Shaghaghi¹, Stephen Kadlecek¹, Mehrdad Pourfathi¹, Sarmad Siddiqui¹, Profka Harrilla¹, and Rahim R. Rizi^1
1Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States

In order to develop a more comprehensive understanding of lung metabolism, we investigated the underlying mechanism of pulmonary metabolic changes in the presence of several notable compounds with a known effect on the biochemical activity of perfused lungs. These compounds included dichloroacetate, a PDK inhibitor; glutathione, an antioxidant and a LDH inhibitor; ascorbate, an antioxidant; dehydroascorbate, the oxidized form of ascorbate; and alpha-lipoic acid, a metabolism modifier. Among these compounds, ascorbate had the most significant effect on PDH flux. In a comparison of the effects, we concluded that the mechanism of ascorbate effect is not due to its antioxidant properties.

Caroline D. Keenan¹, Mehrdad Pourfathi¹, Nicholas N. Kuzma¹, Stephen J. Kadlecek¹, and Rahim Rizi^1
1Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Recent advancements in the production of hyperpolarized gases via solid-state DNP methods offer an attractive alternative for in-vivo lung magnetic resonance imaging. On evaluating the effect of the sample composition on the Xe-129 DNP time constants we find that simple reductions in the radical concentration leads to significant gains.

Caroline D. Keenan¹, Mehrdad Pourfathi¹, Nicholas N. Kuzma¹, Stephen J. Kadlecek¹, and Rahim Rizi^1
1Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Building on recent advances in low temperature DNP methods for producing hyperpolarized (HP) Xe-129 for MRI applications, we explore DNP efficiency of homogeneously mixed Xe/1-propanol/trityl radical mixtures in the solid-state using a newly developed apparatus and evaluate the utility of NMR observables as probes of sample heterogeneity.

Cornelius von Morze¹, Peder EZ Larson¹, Hong Shang¹, and Daniel B Vigneron^1
1Dept. of Radiology & Biomedical Imaging, UCSF, San Francisco, CA, United States

Similar to pyruvate, neat [¹³C]lactic acid appears to be the best form of lactate for dissolution DNP. Unfortunately the neat acid is prone to form a lactide dimer which overlaps spectrally onto product alanine. We investigated the use of a spectrally selective pre-saturation pulse sequence to eliminate dimer signal prior to hyperpolarized metabolic experiments in vivo.

Keita Saito¹, Shingo Matsumoto¹, Yoichi Takakusagi¹, Masayuki Matsuo¹, H Douglas Morris², Hellmut Merkle², Martin J Lizak², Jeeva P Munasinghe², Nallathamby Devasahayam¹, Sankaran Subramanian¹, James B Mitchell¹, and Murali C Krishna^1
1Radiation Biology Branch, National Cancer Institute, Bethesda, Maryland, United States, ²National Institute of Neurological Disorder and Stroke, Bethesda, Maryland, United States

We investigated effects of an mTOR inhibitor rapamycin on pyruvate metabolism in squamous cell carcinoma (SCC) implanted in mice leg using ¹³C-MRI with hyperpolarized [1-¹³C]pyruvate. The signal of [1-¹³C]pyruvate and [1-¹³C]lactate were detected in SCC tumor immediately after hyperpolarized [1-¹³C]pyruvate injection. [1-¹³C]lactate to [1-¹³C]pyruvate ratio (Lac/Pyr) in the SCC tumors increased as tumor grew in non-treated control mice, whereas it significantly dropped after 2 days of rapamycin treatment. So, mTOR inhibition causes decrease of LDH activity in SCC tumor, and lactate to pyruvate ratio monitored using hyperpolarized ¹³C-MRI would become a useful marker for tumor response to therapy.

Marc S Ramirez¹, Jaehyuk Lee¹, Yunyun Chen², Christopher M Walker¹, Stephen Y Lai², and James A Bankson^1
1Department of Imaging Physics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States, ²Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, TX, United States

Spin-echo sequences offer several advantages for hyperpolarized MRSI, yet are challenging due to potential signal loss from the combination of flowing spins and lengthy 180° refocusing pulses. In this work, we developed and evaluated a multi-echo radial MRSI sequence in which a gradient-echo is used to measure the vascular input function of HP [1-¹³C] pyruvate in the blood and a train of spin-echoes is used to enhance the signal-to-noise of tumor measurements. The initial feasibility of this sequence was evaluated in dynamic HP phantoms ex vivo and in a murine model of anaplastic thyroid cancer in vivo.

Haifeng Zeng^1,2, Jiadi Xu^1,2, Joseph Gillen^1,2, Michael T. McMahon^1,2, Dmitri Artemov², Jean-Max Tyburn³, Joost A.B. Lohman⁴, Ryan Mewis⁵, Kevin D. Atkinson⁵, Gary G.R. Green⁵, Simon B. Duckett⁵, and Peter C.M. van Zijl^1,2
1Kirby Center, Kennedy Krieger Institute, Baltimore, MD, United States, ²Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States,³Bruker BioSpin GmbH, Silberstreifen, Rheinstetten, Germany, ⁴Bruker UK Limited, Banner Lane, Coventry, United Kingdom, ⁵Department of Chemistry, University of York, Heslington, York, United Kingdom

Hyperpolarization can provide improved sensitivity for NMR, recently enabling the real-time monitoring of metabolism in vivo. Among the parahydrogen polarization techniques, the signal amplification by reversible exchange (SABRE) approach does not require chemical modification of substrate to polarize. Traditionally, methanol-d4 was used as solvent, which is not suitable for injection into animals. We therefore investigated the possibility of SABRE polarization in more compatible solvents namely DMSO, ethanol and water. In this work, we polarized 3-amino-1,2,4-triazine, pyrazinamide and isoniazid. In methanol-d4, up to -1400 times enhancement was obtained, corresponding to 8% polarization. In water, up to -65 times enhancement was obtained.

Markus Durst^1,2, Ulrich Koellisch^1,2, Concetta Gringeri³, Martin A. Janich², Giaime Rancan^2,3, Annette Frank³, Florian Wiesinger², Marion I. Menzel², Axel Haase¹, and Rolf F. Schulte^2
1IMETUM, Technische Universität München, Garching, Germany, ²GE Global Research, Garching, Germany, ³Klinikum rechts der Isar, Technische Universität München, München, Germany

Dynamic nuclear polarisation has enabled real-time metabolic imaging of pyruvate and its metabolites. Conventional imaging sequences do not account for intersubject variations in biological parameters such as perfusion. A fully automatic realtime bolus tracking sequence for hyperpolarised substrates is presented which starts the imaging acquisition at a defined point on the bolus curve. This reduces artefacts, allows for a more efficient use of hyperpolarised magnetisation and enables a more reliable and consistent quantification of metabolic activity. Using a copolarised urea and pyruvate injection, spectrally selective tracking on urea allows obtaining localised bolus tracking information without depleting the pyruvate signal.

Mehrdad Pourfathi^1,2, Caroline D. Keenan¹, Nicholas N. Kuzma¹, Stephen J. Kadlecek¹, and Rahim R. Rizi^1
1Radiology, Universtiy of Pennsylvania, Philadelphia, PA, United States, ²Electrical Engineering, Universtiy of Pennsylvania, Philadelphia, PA, United States

DNP of 129Xe has the potential to be used for clinical application in MR imaging of the lung parenchyma and structure. Achieving high polarization values are paramount to achieving this goal. Here we demonstrate the utility of pellet formation (on the mm scale) for substantial gains in DNP efficiency in the solid state.

Heeseung Lim¹, Nevin McVicar¹, Francisco M Martinez-Santiesteban¹, Robert Bartha^1,2, and Timothy J Scholl^1,2
1Medical Biophysics, Western University, London, Ontario, Canada, ²Robarts Research Institute, Western University, London, Ontario, Canada

The pH gradient between intracellular and extracellular space changes in tumor. Tumors have a more alkaline pHi and a more acidic pHe. In the current study, pHi and pHe spatial distribution maps are measured in a glioma brain tumor rat model using CEST ¹H-MRI and hyperpolarized ¹³C-MRS respectively. Measured pHi and pHe in normal and tumor tissue are consistent with previous work. The pH maps demonstrate an increased transmembrane pH gradient, ∆pH ≈ 0.14 in the glioma compared to contralateral brain tissue, ∆pH ≈ -0.34. This work represents to the author’s best knowledge the first in vivo quantitative pH-gradient mapping.

Albert P Chen¹ and Charles H Cunningham^2,3
1GE Healthcare, Toronto, ON, Canada, ²Imaging Research, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, ³Deptartment of Medical Biophysics, University of Toronto, Toronto, ON, Canada

In the first in human hyperpolarized 13C metabolic imaging study in prostate cancer patients, spectroscopic based chemical shift imaging technique was utilized to acquire spatially localized hyperpolarized [1-13C] pyruvate and [1-13C]lactate images from a single imaging window. Imaging based approaches utilizing selective excitation of a specific metabolite has been developed in recent years to enable acquisition of temporally resolved 13C metabolic imaging data throughout the time course of substrate infusion and its metabolic conversions. In this study, a comparison between a spectral-spatial EPI sequence designed for dynamic hyperpolarized 13C metabolic imaging and the standard CSI technique was performed in vivo.

Vincent Breukels¹, Cees F.J. Jansen², Jack J.A. van Asten¹, Jan W.M. van Os³, Andrea Capozzi⁴, P. Jan M. van Bentum³, Arnaud Comment⁴, and Tom W.J. Scheenen^1
1Radiology, Radboud University Medical Center, Nijmegen, Gelderland, Netherlands, ²Urology, Radboud University Medical Center, Nijmegen, Gelderland, Netherlands, ³Institute for Molecules and Materials, Radboud University, Nijmegen, Gelderland, Netherlands, ⁴Laboratory for Functional and Metabolic Imaging, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

In-vitro experiments of hyperpolarized ¹³C substrates is a valuable tool to study normal and pathogenic metabolic processes. Commonly these experiments are performed in cell suspensions containing between 25 – 100 million cells. We developed a low volume, low number of cells setup. Using two prostate cancer cell lines we show that accurate quantification of metabolic conversion and perfect resolution (< 1Hz linewidth) can be obtained with as little as two million cells. Our setup expands the use of hyperpolarized MR beyond immortalized cell lines, such as primary cell cultures, for which high number of cells cannot be obtained.

Concetta Valeria Gringeri¹, Ulrich Koellisch^2,3, Annette Frank⁴, Rolf Schulte³, Axel Haase², Markus Schwaiger⁴, and Marion Irene Menzel^3
1Institute of Nuclear Medicine, Klinikum rechts der Isar, TUM, Munich, Bayern, Germany, ²IMETUM, TUM, Munich, Bayern, Germany, ³GE Global Research, Munich, Bayern, Germany, ⁴Institute of Nulcear Medicine, Klinikum rechts der Isar, TUM, Munich, Bayern, Germany

Prostate cancer is the most common cancer in the elderly men and the second leading cause of cancer death in men. Prostate tumor as well as other cancers is characterized by altered energy metabolism and up-regulation of fatty acid synthesis. Hyperpolarized 13C-acetate can be used to investigate prostate tumor metabolism through measurement of the tracer uptake and the metabolic conversion to Acetyl-carnitine (ALCAR) by developing a SNR optimal pulse sequence. An increase by time of acetate uptake was detected in the tumor region allowing to define the time evolution of the signal in tumor and blood vessels. This study reveals that the visualization of prostate cancer with HP 13C-acetate is feasible in rats. Such baseline data could be important when following the modifications in metabolism and to monitor FAS expression in prostate cancer. Further investigations have to be done to evaluate the possibility to correlate cancer aggressiveness with quantitative analysis of prostate cancer metabolism and HP 13C-acetate tumor uptake.

Gunthard Lykowsky¹, Thomas Christian Basse-Lüsebrink¹, Thomas Kampf², Michael Hess³, Stephanie Weibel³, Aladar A. Szalay⁴, Peter Michael Jakob^1,2, and Daniel Haddad^1
1Research Center for Magnetic Resonance Bavaria e.V., Würzburg, Bavaria, Germany, ²Department for Experimental Physics 5, University of Würzburg, Bavaria, Germany,³Department of Biochemistry, University of Würzburg, Bavaria, Germany, ⁴Genelux Corporation, San Diego, CA, United States

Within the last few years, 19F MRI was successfully applied to numerous research questions. For 19F-based cell tracking, ex-vivo MRI in combination with immunohistochemistry is often performed to validate in-vivo findings. Unfortunately, due to different sample geometries and sizes, the correlation of the different imaging modalities is limited. For 1H MRI, coils optimized for imaging of histological samples have been successfully applied. The current work expands the concept of 1H MRI on histological tissue samples to 1H/19F MRI using a double-tunable surface coil, thus allowing correlation between the 1H/19F MR data and histology.

Il Minn¹, Amnon Bar-Shir^1,2, Jeff W. M. Bulte^1,2, Paul B. Fisher³, Assaf A. Gilad^1,2, and Martin G. Pomper^1
1The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, United States, ²Cellular Imaging Section, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, United States, ³Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States

We developed a molecular-genetic imaging approach to accomplish tumor-specific expression of a reporter gene based on chemical exchange saturation transfer (CEST) MRI. The lysine-rich protein (LRP), a CEST reporter, was expressed under the control of the PEG-Prom, which is tumor-specific, in 9L rat glioma cells (9L^PEG-LRP). 9L^PEG-LRP cells transplanted to a mouse brain showed higher CEST contrast compared to those from wild type cells. Here we show the feasibility of using a CEST-reporter gene under a tumor-specific promoter. This is the first step toward a systemic delivery of a PEG-Prom:LRP vector, which allows visualization of malignant tissues with CEST MRI.

Anna V Naumova^1,2, Nathan J Palpant^2,3, Niranjan Balu^1,2, Xia Shen^1,4, Chun Yuan^1,5, and Charles E Murry^2,3
1Radiology, University of Washington, Seattle, WA, United States, ²Center for Cardiovascular Biology, University of Washington, Seattle, WA, United States, ³Pathology, University of Washington, Seattle, WA, United States, ⁴Medicine, University of Washington, Seattle, WA, United States, ⁵Bioengineering, University of Washington, Seattle, WA, United States

We propose an integrative approach to monitor transplanted cells non-invasively by combining MRI based structural and functional evaluation with other imaging modalities such as bioluminescence imaging, fluorescence and PET. For this, we engineered a novel genetically-based sensing system consisting of ferritin, luciferase, GCaMP3, and HSV1-tk, which makes graft detectable by multiple imaging modalities. Human embryonic stem cell line expressing quadruple gene reporter demonstrated T2 shortening effect in MRI, strong bioluminescence and fluorescence properties as well as ganciclovir sensitivity. This integrative approach enables longitudinal non-invasive monitoring of the transplanted cells.

Conrad Steven Martin¹, Min-Chi Ku¹, Stefano Lepore¹, Helmar Waiczies^1,2, Andreas Pohlmann¹, Jan Hentschel¹, Matthias Dieringer^1,2, Thoralf Niendorf^1,2, and Sonia Waiczies^1,3
1Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine, Berlin-Buch, Berlin, Germany, ²MRI.TOOLS GmbH, Berlin, Germany, Berlin-Buch, Berlin, Germany, ³Experimental and Clinical Research Center, Berlin, Germany, Berlin-Buch, Berlin, Germany

19F MRI is used to track the movement of dendritic cells labeled with 19F nanoparticles in their progression through the lymphatic system in the hindquarters of mice. Specific quantitative and temporal data is collected by the use of Point resolved 19F spectroscopy. This has significant implications in human dendritic cell treatments.

Clemens Diwoky¹, Daniel Liebmann², Dirk Strunk³, and Rudolf Stollberger^1
1Graz University of Technology, Graz, Austria, ²Stem Cell Research Unit, Dept. of Hematology, Univ. Clinic of Internal Medicine, Medical University of Graz, Graz, Austria,³Experimental and Clinical Cell Therapy Institute, Paracelsus Medical University, Salzburg, Austria

Within this study we show that for punctuate paramagnetic structures the positioning of the perturber relative to the imaging sampling grid has a notable impact on the signal decrease of the acquired voxel. This effect can be employed in order to boost the contrast of labelled cells if the underlying 3D GRE dataset is zeropadded and a minimum intensity projection between the sub-voxel sampling points is calculated. Simulations and in-vitro cell phantom experiments are used to confirm our theory. The results show a remarkable gain in negative contrast for iron-oxide labelled cells.

Jason Lamanna^1,2, Juanmarco Gutierrez², Lindsey Urquia², Natalia Grin², Jonathan Riley², Jaclyn Espinosa³, Thais Buchman², John Oshinski⁴, and Nicholas Boulis^2
1Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, United States, ²Neurosurgery, Emory University, Atlanta, GA, United States,³Surgery, Emory University, GA, United States, ⁴Radiology, Emory University, GA, United States

Clinical investigations of cell-based therapies transplanted in to the spinal cord do not have a reliable method of confirming graft delivery or survival. We demonstrate a straightforward approach to label human neural progenitor cells with ferumoxytol and track them in the spinal cord of a large animal.

Casey Y. Lee^1,2, R. Terry Thompson^1,2, Frank S. Prato^1,2, Donna E. Goldhawk^1,2, and Neil Gelman^1,2
1Medical Biophysics, Western University, London, ON, Canada, ²Imaging Program, Lawson Health Research Institute, London, ON, Canada

We have investigated the dependence of transverse relaxation rate (R2) on interecho time (2τ) in cells labeled with iron using expression of MagA, a putative iron transport gene. This dependence was analyzed using a mathematical model previously developed for iron-containing tissues. The model provided values for the “spatial correlation length” (distance scale of microscopic magnetic field variation), in iron-supplemented MagA-expressing cells, that were smaller than those previously obtained in iron-containing tissues. In addition to improving our understanding of iron distribution in these systems, our results should provide insight into the development of more iron-specific strategies to detect these cells.

Joseph E Kobes¹, George I Georgiev², Anthony V Lewis³, Horacio L Rilo³, Zain Khalpey³, and Mark D Pagel^4
1Biomedical Engineering, University of Arizona, Tucson, AZ, United States, ²Department of Surgery, University of Arizona, Tucson, Arizona, United States, ³Department of Surgery, University of Arizona, Tucson, AZ, United States, ⁴Department of Biomedical Engineering, University of Arizona, Tucson, Arizona, United States

Re-seeding organ scaffolds with a patient’s own cells is a promising approach to improve organ transplant procedures. This study investigated whether T2-weighted MRI can track the reseeding of murine liver scaffolds. Liver cells were labeled with iron oxide nanoparticles that were coated with polystyrene, fluorophore, protamine sulfate, and glutamine. An acellularized mouse liver was re-perfused with the iron-labeled cells. T2-weighted MRI monitored initial sparsely populated cell loading, and heavily populated cell load after 8 days of cell growth, which was confirmed with confocal microscopy and SEM of liver biopsies. These findings demonstrate that MRI can track re-cellularization of acellularized organs.

Ulysse Gimenez¹, Michèle El Atifi², Hélène Lajous¹, Marie Bidart², Pascal-Henry Fries³, Francois Berger¹, and Hana Lahrech^1
1CEA-Clinatec, Grenoble, France, ²Grenoble Institute of Neurosciences, La Tronche, France, ³Inac, CEA, Grenoble, France

This study is focused on the cellular MRI using ultra-small super-paramagnetic (USPIO) nanoparticles. U937 macrophages are labeled with Molday Ion RhodamineB (MIRB). Cell labeling was characterized in vitro, cell proliferation and viability were not affected by the MIRB internalization. In vitro experiments were conducted at different cell concentrations and a longitudinal in vivo study was achieved. This study shows which MRI parameter (T2*, T2, or T1) is more suitable to track magnetically labeled cells in vivo and attests the ability to quantify labeled U937 cell concentration in a longitudinal study.

Moussa Chehade^1,2, Amit K. Srivastava^2,3, and Jeff W. M. Bulte^2,3
1Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, United States, ²Cellular Imaging Section, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, United States, ³Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States

Among the current challenges in cell transplantation research is the need to monitor cell targeting and survival in pre-clinical models using in vivo imaging. To improve upon current techniques, we developed a method to co-register BLI and MR images of transplanted cells using a specialized animal holder and an a priori spatial transformation paradigm. In vivo testing using ES cell transplants in mice showed that this multimodal approach can visualize cell location with higher accuracy and resolution while providing a more sensitive measure of cell survival than could be obtained with a single imaging modality.

Neil C Talbot¹, Paul Graninger¹, Dwayne Roach^1,2, Erik M Shapiro², Wesley M Garrett¹, and Thomas J Caperna^1
1Beltsville Agricultural Research Center, USDA, Beltsville, MD, United States, ²Department of Radiology, Michigan State University, East Lansing, MI, United States

Many severe, progressive liver diseases may be amenable to hepatocyte transplantation. PICM-19 cells are bipotent liver parenchymal cells derived from pig ESCs and are promising for swine regenerative medicine models of liver disease and for potential human xenotransplantation. Here we demonstrate that magnetic labeling of PICM-19 hepatocytes with MPIOs does not impact the phenotypic or functional properties of these cells, paving the way for their use in MRI-based cell tracking of liver regenerative medicine paradigms. Further, these experiments demonstrate the usefulness of functional assays, rather than detection of cell-surface CD markers for studying effects of magnetic particles on labeled cells.

Kai D. Ludwig¹, Jeremy W. Gordon¹, Myriam N. Bouchlaka², Christian M. Capitini², Bryan P. Bednarz^1,3, and Sean B. Fain^1,3
1Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin, United States, ²Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin, United States,³Radiology, University of Wisconsin-Madison, Madison, Wisconsin, United States

Tumor-specific immunotherapy is emerging as a novel treatment paradigm for patients with metastatic tumors that are incurable with conventional therapies. Natural killer (NK) cells have shown anti-tumor effects against hematological and non-hematological cancers. Often, lack of knowledge on trafficking patterns limits the efficacy of adoptively transferred NK cell’s anti-tumor response. We propose to use an MRI tracer perfluoropolyether agent to detect immune cells in-vivo. Isolated, ¹⁹F-labeled NK cells were injected into a mouse and ¹⁹F MRI detected signal accumulation in a lymphoid tumor. However, ¹⁹F signal contamination was observed from isoflurane anesthetic requiring ketamine/xylazine as an anesthetic in future work.

Ryusuke Nakai^1,2, Narufumi Kitamura¹, and Hiroo Iwata^1
1Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan, ²Kokoro Research Center, Kyoto University, Kyoto, Japan

In this study, we developed a labeling method for islet cells with superparamagnetic iron oxide particles (SPIOs) based on DNA hybridization, which has been successfully applied to cell surface modification. The labeling efficiency of this method was evaluated by MRI. The SPIO-labeled islet cells could be clearly detected as dark spots by T2*-weighted MR image, whereas non-labeled islet cells could not be detected. The method is also likely to be applicable for use with other cells, such as stem cells, and for labeling at multiple sites by changing the DNA sequence.

Stephanie Seah¹, Abu Bakar Ali Asad¹, Richard Baumgartner², Dai Feng², Donald S. Williams³, Elaine Manigbas⁴, John D. Beaver⁴, Torsten Reese¹, Brian Henry¹, Jeffrey L. Evelhoch³, and Chih-Liang Chin^1
1Translational Medicine Research Centre, MSD, Singapore, Singapore, ²Biometrics Research, BARDS, Merck & Co. Inc, Rahway, New Jersey, United States, ³Imaging, Merck & Co. Inc, West Point, Pennsylvania, United States, ⁴Imaging, Maccine Pte Ltd, Singapore, Singapore

We have established an awake non-human primate (NHP) imaging platform and exploited it to delineate brain activities elicited by buprenorphine (0.03 mg/kg iv) under awake and anesthetized phMRI. We found buprenorphine significantly activated brain regions including, thalamus, striatum, frontal and cingulate cortices (paired t-test, versus saline vehicle, p<0.05, n=4) in awake NHPs, whilst no significant change was observed under anesthetized imaging. Additionally, activated brain areas agree with -opioid receptor distribution depicted by [6-O-[¹¹C]methyl]buprenorphine ([¹¹C]BPN) PET study in baboons and previous buprenorphine phMRI data in human and conscious rats. Our work highlights the utility of awake NHP phMRI for translational research.

Geralda A.F. van Tilborg¹, Pavel Yanev¹, Kristel W.M. Boere², Tina Vermonden², Annette van der Toorn¹, Wim E. Hennink², and Rick M. Dijkhuizen^1
1Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, Utrecht, Netherlands, ²Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, University Utrecht, Utrecht, Netherlands

Hydrogels have been suggested as novel drug carrier system for sustained release of therapeutic proteins in several disorders, including stroke. This study shows that biodegradable hydrogels, consisting of thermosensitive triblock polymers and thiolated hyaluronic acid, release ≥ 80% of their gadolinium-labeled albumin load within 2 days, both in vitro and in the brain of living animals. The presented MRI setup provides a unique opportunity to non-invasively monitor protein delivery to the brain through implanted hydrogels in living animals, which could aid in the development and assessment of such innovative drug carrier systems for prolonged drug delivery to injured brain tissue.

Nina F Schwenzer¹, Marinus Schmid¹, Sergios Gatidis¹, Holger Schmidt^1,2, Cornelia Brendle¹, Christian la Fougère³, Claus D Claussen¹, Christina Pfannenberg¹, and Christina Schraml^1
1Diagnostic and Interventional Radiology, Dept. of Radiology, University Hospital Tübingen, Tübingen, BW, Germany, ²Preclinical Imaging and Radiophramacy, Dept. of Radiology, University Hospital Tübingen, BW, Germany, ³Nuclear Medicine, Dept. of Radiology, University Hospital Tübingen, Tübingen, BW, Germany

Recently introduced whole body MR/PET systems allow for assessment of MR- and PET-information within one examination. Furthermore, characterization of tissue properties is possible with high alignment quality of PET and MRI. In the present study, the composition and glucose utilization of bone marrow throughout the human skeleton in vivo was assessed with respect to the fat content using a simultaneous MR/PET scanner. Additionally, the correlation with anthropometric and endocrinological factors on bone marrow composition and metabolic activity such as age, body mass index and blood glucose level were analyzed.

Xiaolei Song^1,2, Tao Yu^1,3, Deepak Kadayakkara¹, Kannie W Y Chan^1,2, Yuan Qiao⁴, Jeff W M Bulte^1,2, Peter CM van Zijl^1,2, Justin S Hanes³, and Michael T McMahon^1,2
1Division of MR Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University, Baltimore, Maryland, United States, ²F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, United States, ³Center for Nanomedicine, The Johns Hopkins University, Baltimore, Maryland, United States, ⁴The Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and Sidney Kimmel Cancer Center at Johns Hopkins Medical Institute, Maryland, United States

Nanocarriers designed for imaging are becoming a powerful tool in oncology, allowing not only tumor detection but also assessment of tumor blood vessel permeability. Liposomes loaded with non-metallic diaCEST MR agents enable evaluation of the efficacy of tumor targeting. Recently a new family of CEST agents was reported, i.e., salicylic acid (SA) and analogues, which contain labile protons with large resonance shifts from water. We developed a series of SA-analogue liposomes for CEST MRI. Of these, 2,4-Dihydroxybenzoic acid, a fruit metabolite, showed the best liposomal retention (>40%) in vitro and also in vivo in mice bearing B16 melanomas, namely 3% CEST contrast.

Dario Livio Longo^1,2, Fatima Zzahra Moustaghfir³, Lorena Consolino^1,2, Giuseppe Digilio⁴, and Silvio Aime^1,2
1University of Turin, Torino, Italy, ²Molecular Imaging Center, University of Turin, Torino, Italy, ³University of Vrije Brussels, Brussels, Belgium, ⁴Environmental and Life Science, University of Eastern Piedmont "Amedeo Avogadro", Alessandria, Italy

Molecules possessing exchangeable proton pools may be selectively imaged within the MRI-CEST modality. Due to the inherent low sensitivity of this technique, high dosages are required to provide enough contrast, thus limiting possible in vivo application to molecules with high LD50 levels. In this study we explored the CEST properties of several pharmaceutical excipients, due to their high safety profiles. We found that most of them were able to generate sufficient CEST saturation transfer contrast for in vivo applications. Intravenous injection into two different tumor bearing mice (breast and melanoma tumor models) showed that it was possible to monitor their uptake by CEST imaging.

Michael Oluwaseun Dada¹, Bamidele Omotayo Awojoyogbe¹, Simona Baroni², and Samarendra Mohanty^3
1Department of Physics, Federal University of Technology, Minna, Niger State, Nigeria, ²Invento Laboratory, Molecular Biotechnology Center (MBC), Torino, Turin, Italy,³Department of Physics, Biophysics and Physiology group, University of Texas, Arlington, Texas, United States

Sickle cell disease (SCD) is an inherited disorder of hemoglobin structure that has no established cure in adult patients. The most important pathophysiologic event in sickle cell anemia, which explains most of its clinical manifestations, is vascular occlusion; this may involve both the micro- and macrovasculature1. The primary process that leads to vascular occlusion is the polymerization of sickle hemoglobin (Hb) on deoxygenation, which in turn results in distortion of the shape of red blood cells (RBC), cellular dehydration, and decreased deformability and stickiness of RBC, which promotes their adhesion to and activation of the vascular endothelium1. SCD has been regarded as a molecular disease without any established cure. Finding a realiable cure for this disease may be dependent on much we know about the molecular processes that lead to it and how we could possibly represent them in terms of images for classical observation. This study presents a contribution to the understanding of SCD using the Bloch – Torrey equation so that we can easily represent the associated chemical processes in MRI images. Vascular occlusion is used to describe any form of blockage to blood vessels.

Pedro Ramos-Cabrer^1,2, Francois Fay¹, Brenda L. Sánchez-Gaytan¹, Teresa Arias^3,4, Jun Tang¹, José Castillo², Valentín Fuster^3,4, Zahi A Fayad¹, and Willem J. M. Mulder^1
1Translational and Molecular Imaging Institute (TMII), Icahn School of Medicine at Mount Sinai, New York, NY, United States, ²Department of Neurology, Clinical Neurosciences Research Laboratory, University Clinical Hospital of Santiago, Health Sciences Institute of Santiago (IDIS), Santiago de Compostela, Spain, ³Department of Cardiology, Zena and Michael A. Weiner Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States, ⁴Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

Labeling of bio-mimicking molecules such as HDL lipoprotein with imaging probes is a very interesting feature of molecular imaging techniques. However, self-aggregating systems are formed under delicate balances of non-covalent molecular interactions that are modified by the introduction of imaging probes. Here we describe how, over certain thresholds, the introduction of high amounts of a gadolinium loaded lipids in nascent HDL nanoparticles do not further increase the magnetic relaxivities of HDL (as desired), but lead in turn to the formation of large aggregates, that no longer can be defined as HDL, and that will potentially present different in vivo properties.

Miriam Schwalm¹, Lydia Wachsmuth², Florian Schmid², Cornelius Faber², and Albrecht Stroh^1
1Institute of Microscopic Anatomy & Neurobiology - Research Group Molecular Imaging & Optogenetics, Johannes Gutenberg-University Mainz, Mainz, Rheinland-Pfalz, Germany, ²Department of Clinical Radiology, University of Münster, Nordrhein-Westfalen, Germany

Revealing the neuronal underpinnings of fMRI requires monitoring of suprathreshold spiking. We implemented the combination of optical Ca2+ recordings with BOLD fMRI in rat somatosensory cortex and recorded Ca2+ and BOLD signals in two brain states: in Up/Down state, sensory stimulation did not lead to BOLD activation, despite initiation of Ca2+ waves. In persistent Up state, we recorded primary neuronal Ca2+ responses, and BOLD activation. The duration of the BOLD response depended on the duration of stimulus trains, even though Ca2+ transients revealed adaptation of the neuronal response. Our data suggests that neuronal spiking plays a minor role in BOLD.

Diethard Schmidt¹, Philippe Appenzeller², Martin Hüllner², Felix Kuhn², Daniel Schmid², Andreas Boss², Gustav von Schulthess², and Patrick Veit-Haibach^2
1University Hospital Zurich, Zurich, Kanton Zurich, Switzerland, ²University Hospital Zurich, Zurich, Switzerland

Comparison of PET/MRI and PET/CT for abdominopelvic oncologic lesions with evaluation of three MR sequences [Ultra fast gradient echo (GRE), balanced gradient echo (bGRE) and ultra fast spin echo (SE)]

Amine Samoudi¹, Karen Van Audenhaege², Günter Vermeeren¹, Michael Poole³, Roel Van Holen², Luc Martens¹, and Wout Joseph^1
1INTEC, Ghent University/iMinds, Ghent, Belgium, ²ELIS, Ghent University/iMinds, Ghent, Belgium, ³INM-4, Forschungszentrum Jülich GmbH, Jülich, Germany

This study investigates eddy currents in the collimator due to gradient coils, for different resistivities of tungsten materiel. The system is meant to be used for a small animal SPECT/MRI. Two electromagnetic simulation platforms, SEMCAD-X and FEKO, were employed for simulating the gradient coils with the collimator. Results showed that for higher values of resistivity, lower current densities on the collimator are obtained and thus lower eddy current effects, reducing deviations from the expected values of the gradient. Characterizing eddy currents and using an improved design of the gradient should reduce the eddy current effect on the collimator.

Andrea Galisova¹, Daniel Jirak¹, Eva Fabryova², Vit Herynek¹, Eva Dovolilova², Jan Kriz², and Milan Hajek^1
1MR Unit, Department of Diagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic, Czech Republic, ²Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic, Czech Republic

Sufficient blood supply to the transplanted cells is crucial for their survival and can be enhanced by implantation of stem cells. We examined the effect of stem cells on vascularization of artificial scaffolds intended for pancreatic islet transplantation by Dynamic Contrast Enhancement MR. Presence of genetically modified stem cells was confirmed by bioluminescence imaging. We observed increased perfusion in the devices simultaneously with optical signal within 2 months following stem cells implantation. Our results indicate that stem cells improve vascularization inside the chambers what ameliorates the transplantation outcome.

Cornelia Brendle¹, Holger Schmidt², Anja Oergel¹, Ilja Bezrukov², Mark Mueller³, Christina Pfannenberg¹, and Nina Schwenzer^1
1Radiology, Tuebingen, Baden-Wuerttemberg, Germany, ²Preclinical Imaging, Tuebingen, Baden-Wuerttemberg, Germany, ³Nuclear Medicine, Tuebingen, Baden-Wuerttemberg, Germany

In this study the routinely used segmentation-based PET attenuation correction map in hybrid MR/PET was analyzed concerning artifacts in general and in suspicious PET positive lesions as well as their impact on PET quantification. Nearly 3 artifacts were found per patient dataset with significant changes of PET quantification in the lungs, at the body contours, around metal implants and in the brain. PET positive lesions especially around metal implants resulted in significant changes of PET quantification. We recommend checking attenuation correction maps for artifacts in routine MR/PET examinations in order to avoid impairment of lesion characterization and differentiation.

Bryan H De La Garza¹, Chakradhar Velagapudi², Hanna E Abboud², Guang Li¹, and Timothy Q Duong^1
1Research Imaging Institute, Department of Radiology/Ophthalmology, Univ. Of Texas Health Science Center, San Antonio, Tx, United States, ²Dept of Medicine-Renal Diseases, Univ of Texas Health Science Center, San Antonio, Tx, United States

Manganese-enhanced MRI (MEMRI) was used to investigate the calcium activity in different layers of the retina of diabetic retinopathy (DR) rats under light and dark adaptation 14 and 30 days after streptozocin injection. In normals, dark adaption lowered inner retina MEMRI activity, increased outer retina activity, but did not affect the choroid when compared to light adaptation. In DR rats compared to controls, MEMRI revealed reduced Mn uptake in the inner, outer, and choroid layers. Differential reduced MEMRI activity in dark was observed in the outer layer in DR rats compared to controls, suggesting outer retina dysfunction at early DR

Byungmok Kim¹, Mun Han¹, Yongmin Chang^1,2, and Hui Joong Lee*^3
1Department of Medical & Biological Engineering, Kyungpook National University, Daegu, Korea, ²Department of Radiology & Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Korea, ³Department of Radiology, Kyungpook National University, Daegu, Korea

The aim of this study is to investigate the central nervous system (CNS) delivery of manganese following intranasal administration form the nasal passage to the CNS, response to different olfactory stimulants. Olfactory bulb in the signal intensity increased about Formic acid and Linalool. Acetone, Normal saline reduced the signal intensity, but there was statistically difference about four stimuli. Change of signal intensity on cerebral cortex, amygdale, pons and cerebellum showed statistical differences according to four stimuli (P<0.05). In conclusion, manganese-enhanced MRI revealed different manganese uptake on olfactory pathway according to different olfactory stimuli, which suggest activity-induced manganese-dependent MRI of olfactory pathway dependant on olfactory function.

Geoffrey Topping¹, Andrew Yung², Paul Schaffer³, Cornelia Hoehr³, Thomas Ruth³, Piotr Kozlowski², and Vesna Sossi^1
1Physics and Astronomy, University of British Columbia, Vancouver, British Columbia, Canada, ²MRI Research Centre, University of British Columbia, Vancouver, British Columbia, Canada, ³Nuclear Medicine, TRIUMF, Vancouver, British Columbia, Canada

Live rats given single injections containing both MnCl2 and Mn-52, and their brains imaged with MRI R1 relaxation rate mapping, as well as positron emission tomography. Post mortem, autoradiographs were also acquired of ex vivo brain slices. Per-voxel differences between baseline and post-injection R1 were converted to Mn concentration using an in vitro derived Mn relaxivity calibration factor. Excellent quantitative agreement between PET and MRI was observed, indicating Mn MRI can produce accurate Mn concentration maps in live rat brain, although although localized discrepancies were observed at high Mn concentrations or when other factors affected the relaxation rate.

Mun Han¹, Da Jung Jung², Kyu Yup Lee², Yongmin Chang*^1,3, and Hui Joong Lee*^4
1Department of Medical & Biological Engineering, Kyungpook National University, Daegu, Korea, ²Department of Otorhinolaryngology & Head and Neck surgery, Kyungpook National University, Daegu, Korea, ³Department of Radiology & Molecular Medicine, Kyungpook National University, Daegu, Korea, ⁴Department of Radiology, Kyungpook National University, Daegu, Korea

Animal models continue to improve our understanding of tinnitus pathogenesis and aid in development of new diagnosis. However, there are no diagnostic biomarkers for tinnitus-related pathophysiology for use in animal. To address this disparity, two complementary methods were combined to examine reliable tinnitus models: manganese-enhanced MRI (MEMRI) and inhibition of the acoustic startle reflex (ASR) test. Salicylate-induced tinnitus resulted in many manganese uptake compared to normal model. Relative to that in controls, high signal intensity is shown in the areas of the cochlea and cochlear nucleus in salicylate group, displaying clear difference in six hour and twelve hour MEMRI image. Our results provide the foundation for future studies correlating the longevity of tinnitus with neuronal activity in the cochlea and specific brain regions.

Chien-Lin Yeh^1,2, Elizabeth Zauber³, Sandy Snyder¹, Zaiyang Long^1,2, and Ulrike Dydak^1,2
1School of Health Sciences, Purdue University, West lafayette, Indiana, United States, ²Dept. of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, United States, ³Dept. of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, United States

While the paramagnetic properties of Mangnaese (Mn) are highly used as contrast agent for MRI, little is known about the spatial distribution of Mn accumulation in human cortical brain areas due to occupational Mn exposure. This study uses 3D T1 mapping to analyze whole brain Mn deposition in a group of welders. Findings of significant Mn accumulation in motor regulation and visuospatial networks are consistent with neuropsychological studies on the neurotoxic effects of Mn exposure, suggesting that the location of Mn accumulation affects the function of the corresponding brain networks.

Aditya N Bade¹, Santhi Gorantla¹, Prasanta Dash¹, Edward Makarov¹, Larisa Y Poluektova¹, Howard E Gendelman¹, Michael D Boska^1,2, and Yutong Liu^1,2
1Pharmacology and Experimental neuroscience, University of Nebraska Medical Center, Omaha, NE, United States, ²Department of Radiology, University of Nebraska Medical Center, Omaha, Omaha, NE, United States

Progressive HIV infection commonly leads to cognitive impairments. Disease complexity for what is commonly called HIV-associated neurocognitive disorders (HAND) is reflected by co-morbid conditions including substance abuse, psychiatric disease, aging, society and environment factors. To date, no reliable diagnostic tests for disease are available. In this study, we used MEMRI to evaluate changes in the brains of humanized mice due directly to HIV-1 infection. We analyzed data in individual neurostructures using a MEMRI-based brain atlas. We showed that decrease in signal enhancement suggests neuronal impairments in brain regions of infected mice, and corresponds to viral load and immune cell losses.

Aditya N Bade¹, Biyun Zhou², JoEllyn McMillan¹, Prabagaran Narayanasamy¹, Ram Veerubhotla¹, Howard E Gendelman¹, Michael D Boska^1,3, and Yutong Liu^1,3
1Pharmacology and Experimental neuroscience, University of Nebraska Medical Center, Omaha, NE, United States, ²Department of Anesthesiology, Tongji Medical College, Huanzhong University of Science and Technology, China, ³Department of Radiology, University of Nebraska Medical Center, Omaha, NE, United States

Quantitative manganese (Mn2+) uptake provides measures of neuronal and glial activities making MEMRI a valuable test for assessment of neurodegenerative processes. However, the prolonged half-life of Mn2+ in brain (51–74 days) limits serial quantitative MR assessments. Previous studies have suggested that N-acetyl-para-aminosalicylic acid (AcPAS), a chelater of manganese may provide an answer. Thus, we determined whether AcPAS could affect Mn2+ enhancement decline and permit its frequent administration for longitudinal studies, PBS used as control. The results suggest that the chelation by AcPAS interfere with the interaction of water molecules and Mn2+ ions, and therefore suppresses Mn2+ T1 shortening effect.

Mohammed Salman Shazeeb^1,2
1Radiology, University of Massachusetts Medical School, Worcester, MA, United States, ²Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA, United States

Diffusion-weighted NMR techniques have established that the ADC of cerebral tissue water decreases during ischemia. However, it remains unclear whether the ADC change occurs due to changes in the intracellular (IC) space, extracellular (EC) space, or both. Past works have measured compartment-specific diffusion coefficients using gadolinium as an EC MR contrast agent which reduces the longitudinal (T1) relaxation time of the EC space. In this study, we investigate an alternative approach by using manganese (Mn2+), which acts as a calcium analogue. Mn2+ uptake by cells causes T1 of IC water to shorten, thus allowing differentiation between the compartmental MR signals.

Tatjana Atanasijevic¹, Theodore L. Roth², Dorian B. McGavern², and Alan P. Koretsky^1
1LFMI, NINDS, NIH, Bethesda, MD, United States, ²NINDS, NIH, Bethesda, MD, United States

There has been increased interest in neuronal tract tracing using Manganese Enhanced Magnetic Resonance Imaging (MEMRI). Typically manganese chloride is administered to an animal by direct injection into the brain. Here it is demonstrated that manganese chloride solution can diffuse through the rat scull bone when applied directly on the exposed scull. Signal enhancement has been observed in the expected neuronal pathway. This offers the possibility of much less invasive manganese delivery method for MEMRI.

Xiaoyong Zhang¹, Jie Song¹, Sha Wang¹, Brenda Robledo¹, Craig L Hill², Shuming Nie¹, and Xiaoping Hu^1
1Department of Biomedical Engineering, Emory University, Atlanta, Georgia, United States, ²Department of Chemistry, Emory University, Atlanta, Georgia, United States

The purpose of this work was to synthesize a new tetramanganese cluster in a POM chelate frame named tetra-manganese Polyoxometalates (Mn4POM) and to evaluate its application as a contrast agent for MRI. X-ray single crystal diffraction showed Mn4POM has the tetra-manganese (Mn4) core within its crystal structure. When cells were exposed to low concentrations of Mn4POM, no cytotoxicity was caused. MRI demonstrated that cells incubated with Mn4POM showed significant increase in R1, compared with cells incubated with MnCl2. Our results indicate Mn4POM is a new candidate contrast agent with better MR contrast than free Mn2+, likely due to the Mn4 core within its crystal structure, suggesting that Mn4POM may also be used for in vivo contrast enhancement.

Chin-Tien Lu¹, Chih-Ching Lai¹, Sheng-Min Huang¹, and Fu-Nien Wang^1
1Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan

Recently, the deuterium oxide(D₂O) has been used as a negative contrast agent for perfusion imaging by indirectly monitoring the infused deuterium via the conventional protonium imaging. It is also noticed that the H/D isotope exchange effect of deuterium can prolong the T₁ and T₂ relaxation of protonium. In this study, we aimed to investigate the contrast mechanism in an environment with macromolecules. The r₁ relaxivity of D₂O is nearly irrelevant to BSA concentration, while the r₂ has a linear correlation with BSA concentration. It is found that the contrast mechanism is sensitive to the macromolecular content.

Guan Wang^1,2, Yingli Fu¹, Shashank Sathyanarayana Hegde¹, Steven M. Shea³, and Dara L. Kraitchman^1,4
1Russell H. Morgan Dept. of Radiology & Radiological Sciences, Johns Hopkins University, Baltimore, MD, United States, ²Electrical & Computer Engineering, Johns Hopkins University, Baltimore, MD, United States, ³Corporate Technology, Siemens Corporation, Baltimore, MD, United States, ⁴Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, MD, United States

Nearly 12% of Americans suffer from peripheral arterial disease (PAD) with stem cell therapies providing a new alternative treatment for the most severe cases. Microencapsulated stem cells (SCs) offer a novel means to transplant mismatched cells to avoid immunorejection and enable tracking using conventional imaging modalities. Using a rabbit model of PAD, we determine the ability of c-arm CT and MRI to serially measure capsule persistence and concentration in an immunocompetent rabbit after xenogenic (Xeno) or allogenic (Allo) SC microcapsule delivery. XenoSCs were as well tolerated as AlloSCs and could be accurately and reproducibly tracked by CT and MRI.

Jianhua Yan¹, Jason Chu-Shern Lim¹, Hoi Yin Loi², Ivan WK Tham^1,3, John James Totman¹, Arvind Kumar Sinha², Swee Tian Quek², and David W Townsend^1,2
1A*STAR-NUS, Clinical Imaging Research Center, Singapore, Singapore, Singapore, ²Department of Diagnostic Radiology, National University Hospital, Singapore, Singapore,³National University Cancer Institute, Singapore, Singapore

Positron emission tomography (PET) with [18F]flurodeoxyglucose (FDG) provides quantitative information regarding cellular glucose metabolism. The standardized uptake value (SUV) is commonly used to evaluate tumor glucose metabolism, which is biomarker for clinical diagnosis of tumor malignancy, disease recurrence, and metabolic response to therapy. Diffusion-weighted MRI (DWI) is also increasingly used in the evaluation of malignant disease. By combining two or more images of the same area with different diffusion weighting, water movement can be quantified as the apparent diffusion coefficient (ADC) . Like the SUV from PET/CT, ADC has been used clinically to differentiate benign from malignant tumors and to assess tumor grade, delineate tumor extent and predict survival3. Results of several studies have suggested an inverse correlation between SUV and ADC across varying malignancies including the first study evaluated on a simultaneous PET/MRI hybrid imaging system4, which has the capability of eliminating registration error due to separate PET/CT and MRI examinations and minimizing potential physiological and treatment changes due to the time interval between the PET and MRI examinations. The purpose of this study is to continue to investigate whether FDG-PET and ADC have significant correlation evaluated on simultaneous PET/MRI.

Tirusew Tegafaw Mengesha¹, Wenlong Xu¹, Badrul Alem Bony¹, Cho Rong Kim¹, Sung June Kim¹, Md. Wasi Ahmad¹, and Gang Ho Lee^1
1Chemistry, Kyungpook National University, Daegu, Korea

Fluorescein surface-modified gadolinium oxide nanoparticles which were synthesized in triethylene glycol were nearly monodisperse in diameter and highly water-dispersible. These nanoparticles can be used as MRI contrast agent as well as optical imaging. This dual imaging capability will increase the possibility of an early observation of disease such as cancer. Magnetic Resonance Imaging (MRI) is primarily a noninvasive medical imaging technique used in radiology to visualize detailed internal structure and limited function of the body

Md Wasi Ahmad¹, Wenlong Xu¹, Badrul Alam Bony¹, Tirusew Tegafaw Mengesha¹, Cho Rong Kim¹, Sung June Kim¹, and Gang Ho Lee^1
1Chemistry, Kyungpook National University, Daegu, Korea

Biological molecules are suitable carriers of ultrasmall nanoparticles for biomedical applications. In this study, we investigate: (1) BSA is a good nanoparticles carrier (2) MR relaxivity measurements revealed that BSA-PEG diacid-ultrasmall Gadolinium oxide nanoparticles (BSA-PEGD-GNPs) had larger r1 and r2 values than those of the molecular Gd-chelates (3) The 3 tesla T2 MR images after injecting the aqueous sample solution of BSA-PEGD-GNPs into the mouse tail vein showed clear negative contrast enhancements, confirming that the sample solution functioned as a T2 MRI contrast agent

Andrea Protti¹, Xuebin Dong¹, Silvia Lorrio², Alkystis Phinikaridou², Begona Lavin², Ajay Shah¹, and Rene Botnar^2
1King’s College London British Heart Foundation Centre of Excellence, London, UK, United Kingdom, ²King's College London, London, UK, United Kingdom

Introduction. The pathophysiological and molecular mechanisms of cardiac remodeling after the onset of MI have been widely studied with histochemistry techniques [1] and imaging techniques such as echocardiography [2] and MRI. Such studies suggest a degradation of the matrix leading to creation of a collagen-based scar with some elastin content. Elastin is important because it may provide a degree of elasticity to the infarcted tissue thus decreasing the risk of myocardial rupture. In this study, we investigated the elastin content of the infarcted myocardium in a mouse model using MRI after injection of the ESMA contrast agent. Areas of uptake and relaxation values over a longitudinal study were estimated.

Wenlong Xu¹, Badrul Alam Bony¹, Tirusew Tegafaw Mengesha¹, Cho Rong Kim¹, Sung June Kim¹, Md. Wasi Ahmad¹, and Gang Ho Lee^1
1chemistry, Kyungpook National University, Teagu, Korea

In this report, magnetic resonance imaging (MRI), and cell labeling (CL) contrast agent of single-phase mixed DyEuO₃ and HoEuO₃ nanoparticles has been synthesized. They were characterized with XRD, FT-IR, TGA, PL, HRTEM, SQUID magnetometer and MRI instrument. There is no appreciable cytotoxicity up to 500 ¥ìM concentration. The synthesized nanoparticles were monodisperse with average diameter (d_avg) of 2 nm. Both samples were found to be paramagnetic and emitted strong red fluorescence. From in vivo MRI experiment we found that the negative contrast had been enhancement on mouse liver and kidneys after the injection of nanocolloid.

Shuhei Murayama^1,2, Jun-ichiro Jo¹, Yuka Shibata², Kun Liang³, Tomofumi Santa², Tsuneo Saga¹, Ichio Aoki¹, and Masaru Kato^2
1Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Chiba, Japan, ²Graduate School of Pharmaceutical Sciences and GPLLI Program, The University of Tokyo, Tokyo, Tokyo, Japan, ³Center for Medical Systems Innovation Summer Internship Program, The University of Tokyo, Tokyo, Tokyo, Japan

We developed a simple method to prepare PEG-based soft nanoparticles that encapsulate dual imaging probes. The nanoparticles were administrated to mice and the pharmacokinetics of the nanoparticles was analyzed by means of MRI, fluorescence spectroscopy, and transmission electron microscopy. The soft nanoparticles were excreted by the mice rapidly through the urine without collapse and without leaking of the probe. The pharmacokinetics of the nanoparticles was not changed by the encapsulated molecules and acute toxicity to mice was negligible. It was expect that these PEG-based soft nanoparticles will be applicable for use as a safe diagnostic agent.

Enza Di Gregorio¹, Giuseppe Ferrauto¹, Stefania Lanzardo¹, Eliana Gianolio¹, and Silvio Aime^1
1Molecular Biotechnologies & Health Sciences, University of Torino, Torino, Italy

Different MRI contrast agents have been developed as blood pool agents and are currently used in clinical and/or pre-clinical applications. One of the issues related to their use deals with their possible extravasations. Herein, we suggest a new way to get rid of this problem by using Gd-labelled RBCs that remain fully confined in the blood vasculature. Since tumor vasculature is one of the most intensively investigated aspects of the tumor growth the evaluation of vascular volume inside tumor region is of huge interest for the tumor staging and for the evaluation of anti cancer treatments.

Chris Lascola¹, Talaignair Venkatraman², Karel Base³, and Haichen Wang^4
1Radiology, Duke University Medical Center, Durham, NC, United States, ²Duke University Medical Center, NC, United States, ³Radiology, Duke University Medical Center, NC, United States, ⁴Neurology, Duke University Medical Center, NC, United States

Gd(III) complexes have proven invaluable for blood pool and interstitial contrast, however their use as targeted intracellular paramagnetic reporters has been less successful. Paramagnetic ligands ideally must not only maintain low molecular weight but also possess favorable chemical properties to enable optimal biodistribution. To meet this challenge, we have investigated a new class of low molecular weight, high spin Fe(III) and Mn(II) chelate complexes based on pyrophosphate and bisphosphonate ligands, respectively, that demonstrate excellent chemical stability, strong relaxivity, and broad potential for derivatization and paramagnetic labeling.

Hyun-Jeong Jeong¹, Min-Kyoung Kang¹, Ki-hye Jung², Soyeon Kim¹, Garam Choi¹, Hee-Kyung Kim¹, Eun-Young Jeon³, Tae-Jeong Kim², and Yongmin Chang*^1,4
1Department of Medical and Biological Engineering, Kyungpook National University, Daegu, Korea, ²Department of Applied Chemistry, Kyungpook National University, Daegu, Korea, ³Institute Biomedical of engineering, Kyungpook National University Hospital, Daegu, Korea, ⁴Department of Diagnostic Radiology and Molecular Medicine, Kyungpook National University, Daegu, Korea

Gadolinium Complex of 1,4,7,10-tetraazacyclododecane-N,N,N,N-1,4,7-triacetic acid (DO3A) Conjugate of tranexamates: A Quest for a Liver-specific Magnetic Resonance Imaging Contrast Agent

Line Hansen^1,2, Francois Fay¹, Anita Gianella¹, Pedro Ramos-Cabrer¹, Bram Priem¹, Brenda Sanchez¹, Aneta J. Mieszawska¹, Robert Langer³, Jørgen Kjems², Zahi A. Fayad¹, and Willem J. M. Mulder^1
1Translational and Molecular Imaging Institute at Icahn School of Medicine, Mount Sinai, New York, NY, United States, ²Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus C, Denmark, ³Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States

Surface-swtichable lipid/PLGA hybrid nanoparticles with an MMP-2 cleavable PEG coating were developed. To enable near infrared optical imaging and MRI, Cy5.5 dyes and Gd-DPTA-lipids were incorporated in their polymeric core and lipid corona, respectively. In vitro studies were performed to show the protease-induced switching and utility of this multifunctional nanoparticle platform.

Miriam Filippi¹, Marisa Ferraretto¹, Gilberto Mulas¹, Jonathan Martinelli², Lorenzo Tei², Mauro Botta², Silvio Aime^1,3, and Enzo Terreno^1,3
1Molecular Biotechnologies and Health Sciences, University of Turin, Turin, Turin, Italy, ²Department of Sciences and Technological Innovation, University of Eastern Piedmont 'A. Avogadro', Alessandria, Italy, ³Center for Preclinical Imaging, University of Turin, Colleretto Giacosa, Turin, Italy

The potential of newly developed nanovesicles, named dendrimersomes, as MRI reporters was investigated by encapsulating the contrast agent Gadoteridol inside the aqueous core or by incorporating a novel dendrimer covalently conjugated to a Gd-complex into the vesicular bilayered membrane. Due to the high membrane permeability, longitudinal relaxivity of encapsulated probes was subjected only to a limited quenching effect. On the other hand, membrane-incorporated probes showed higher relaxivity values that are typical of slowly rotating Gd-chelates. Stability and imaging studies suggested that dendrimersomes may have the potential to act as efficient diagnostic/theranostic MRI agents.

Alexei Bogdanov, Jr¹, Mohammed S Shazeeb¹, Lejie Zhang², and Surong Zhang^1
1Radiology, UMASS Medical School, Worcester, MA, United States, ²Biochemical Pharmacology, UMASS Medical School, Worcester, MA, United States

We developed a strategy enabling synthesis of hybrid iron-oxide gold nanoparticles with very high molar relaxivity in water. Silver-tagged dextran-stabilized iron oxides (IO-Ag) were formed by reacting iron oxides in the presence of diamminesilver(I) nitrate. Incubation of IO-Ag in the presence of tetrachloroauric acid and citrate resulted in the formation of electron dense single-core negatively charged IO-Ag-Au which were stabilized using MPEG-gPLL resulting in stable 65 nm nanoparticles. At 3T, the increase of r2 allowed improving the detectability level by a factor of 10. The obtained nanoparticles could be targeted using antibody fragments and were forming complexes with oligonucleotide duplexes.

Sophie Laurent¹, Dimitri Stanicki¹, Sebastien Boutry², Ludivine Wacheul², Emilien Nicolas², Deborah Crombez¹, Luce Vander Elst¹, Denis Lafontaine^2,3, and Robert N Muller^1,2
1General, Organic and Biomedial Chemistry, NMR and Molecular Imaging Laboratory, UMONS, MONS, Hainaut, Belgium, ²Center for Microscopy and Molecular Imaging, Hainaut, Belgium, ³Laboratory of RNA Metabolism, ULB, Brussels, Belgium

This study reports the synthesis of USPIO as bimodal probes for magnetic resonance and optical imaging. These nanosystems are based on small iron oxide cores surrounded by a thin polysiloxane shell exhibiting carboxylic acid functions. Thanks to these functions, hybrid particles were obtained by conjugating a fluorophore to the superparamagnetic contrastophore. Such modification allowed directly following these USPIO in cellulo, which provided interesting information about their internalization pathway and cellular distribution upon mitosis. Finally, their efficiency as probes for bimodal imaging was emphasized by the observation of their in vivo behavior in mice using magnetic resonance and optical imaging.

Ki-Hye Jung¹, Hee-Kyung Kim², Min-Kyoung Kang², Soyeon Kim², Hyun-Jeong Jeong², Garam Choi², Ji-Ae Park³, Eun-Young Jeon⁴, Tae-Jeong Kim¹, and Yongmin Chang*^2,5
1Department of Applied Chemistry, Kyungpook National University, Daegu, Korea, ²Department of Medical & Biological Engineering, Kyungpook National University, Daegu, Korea, ³Molecular Imaging Research Center, Korea Institute of Radiological & Medical Science, Seoul, Korea, ⁴Institute of Biomedical Engineering, Kyungpook National University, Daegu, Korea, ⁵Department of Diagnostic Radiology and Molecular Medicine, Kyungpook National University, Daegu, Korea

We report the synthesis of 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid (DO3A) derivatives of benzothiazole and their Gd(III) complexes of the type [Gd(DO3A-BTA)(H₂O)] (2a,b) for use as a single molecule theranostic agent. The complexes are not only tumor-specific but also intracellular, enhancing MR images of cytosols and nuclei of tumor cells such as MCF-7, MDA-MB-231, SK-HEP-1, HeLa, and Caki-2. 2a and 2b reveal antiproliferative, activities as demonstrated by GI₅₀ and TGI values obtainable form the cell counting kit-8 (CCK-8) assays performed on these cell lines.

Jiang Zhu^1,2, Eirc Gale¹, Iliyana Atanasova³, and Peter Caravan^1
1Martinos Center for Biomedical Imaging, Charlestown, MA, United States, ²Sichuan Key laboratory of Medical Imaging, Nanchong, Sichuan, China, ³Massachusetts Institute of Technology, Cambridge, MA, United States

Here we describe the synthesis and characterization of a hexameric Mn(II)-based MR contrast agent. The hydration state and other kinetic and thermodynamic parameters were determined by 17O NMR method. The small, compact size of this hexamer exhibits greater relaxivity at low, intermediate and high fields compared to its monomeric analog.The intermediate R and relatively rapid water exchange rate make this Mn-EDTA multimer a good candiate for high-field MRI contrast agent applications.

Patrick Winter¹, Xiaoyang Qi², Zhengtao Chu², Enkhsaikhan Purevjav³, and Jeffrey Towbin^3
1Radiology, Cincinnati Children's Hospital, Cincinnati, OH, United States, ²Hematology and Oncology, University of Cincinnati, Cincinnati, OH, United States, ³Heart Institute, Cincinnati Children’s Hospital, Cincinnati, OH, United States

The Fas ligand (FasL) is a signaling protein that causes programmed cell death, also called apoptosis. An MRI contrast agent targeted to apoptosis can be formulated by incorporating paramagnetic chelates onto SapC-DOPS vesicles. Mice that overexpress FasL in the heart were imaged at 7T with standard cardiac MRI and molecular imaging of apoptosis. Cardiac MRI revealed that the transgenic mice had impaired ejection fraction and left ventricular hypertrophy. Injection of Gd-SapC-DOPS vesicles produced higher signal enhancement in FasL mice compared to the control animals, suggesting myocardial apoptosis in this animal model.

Sebastian Temme¹, Christoph Grapentin², Christine Quast¹, Christoph Jacoby¹, Zhaoping Ding³, Friederike Mayenfels⁴, Jürgen Schrader¹, and Ulrich Flögel^1
1Molecular Cardiology, University of Düsseldorf, Düsseldorf, NRW, Germany, ²Pharmaceutical Technology and Biopharmacy, University of Freiburg, Freiburg, BW, Germany,³Molecular Cardiology, University of Düsseldorf, Düsseldorf, Germany, ⁴University of Freiburg, Freiburg, BW, Germany

Detection of deep venous thrombi which are not accessible by ultrasound is still a serious challenge. Therefore a non-invasive technique for unequivocal identification of those thrombi for diagnosis and subsequent monitoring of antithrombotic therapy would be highly desirable. Therefore we applied a novel sterol-based post-insertions technique to generate stable 2-antiplasmin targeted PFC-NE for the rapid, highly specific and unequivocal identification of freshly developed deep venous thrombi, which might have a potential clinical application in detection of rethrombosis or lung thromboembolism. Moreover, we propose that the sterol-based post-insertion technique is a promising platform to equip PFC-NE with different ligands (peptides, antibodies etc.) for in-vivo 19F MRI of specific targets.

Yuancheng Li^1,2, Run Lin^1,2, Liya Wang^1,2, Jing Huang^1,2, Lily Yang³, and Hui Mao^1,2
1Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, United States, ²Center for Systems Imaging, Emory University, Atlanta, GA, United States,³Department of Surgery, Emory University, Atlanta, GA, United States

One of the major challenges in applications of IONPs for in vivo imaging is the non-specific uptake of the nanoparticles by the macrophages and reticuloendothelial system (RES). Non-specific uptake may lead to lower blood circulation time and introduce interfering background signal, thus substantial reduction in the efficiency of target-directed imaging. In this work, iron oxide nanoparticle molecular imaging probes were modified with a novel anti-fouling poly ethylene glycol based copolymer coating to reduce the non-specific absorption of macromolecules and non-specific uptake by macrophages, thus improve cell targeting.

Anne Schmieder¹, Huiying Zhang¹, Jochen Keupp², Shelton Caruthers², Samuel Wickline¹, Elizabeth Wagner³, and Gregory Lanza^1
1Washington University Medical School, St. Louis, MO, United States, ²Philips Research Laboratories, Hamburg, Germany, ³Johns Hopkins University, Maryland, United States

Angiogenesis is an important constituent of many inflammatory pulmonary diseases, which is poorly understood. Early neovascular expansion in the lungs in preclinical models and patients is very difficult to assess noninvasively, particularly quantitatively. The present study demonstrated that (19)F/(1)H MR molecular imaging with αvβ3-targeted perfluorocarbon nanoparticles can be used to directly measure neovascularity in a rat asthma model. In rats 7, 14, and 21 days after house dust mite induction of asthma, simultaneous (19)F/(1)H MR imaging at 3T revealed a marked (19)F signal in animals 2 h following αvβ3-targeted perfluorocarbon nanoparticles that was significantly greater than the signal found in the saline treated controls. Our results demonstrate that (19)F/(1)H MR molecular imaging with αvβ3-targeted perfluorocarbon nanoparticles provides a means to assess the extent of systemic neovascularization in the lung. This novel application of dual 1H/19F MR molecular imaging is a clinically translatable approach for noninvasive temporal-spatial assessment of lung angiogenesis, which may provide a better understanding about the role of pulmonary angiogenesis in asthma.

Achraf Al Faraj¹, Asma Sultana Shaik¹, and Rabih Halwani^2
1Radiological Sciences, King Saud University, Riyadh, Riyadh, Saudi Arabia, ²PNRCIR, King Saud University, Riyadh, Riyadh, Saudi Arabia

In order to improve the identification and long-term care for patients with COPD, new techniques are required for better assessment of morphological and functional impairment and contribution of each aspect to the patients’ symptoms. Therefore, a noninvasive imaging modality that enables in vivo inflammatory single cell population detection to understand the physiological process in COPD is highly required for both diagnostic purposes and therapeutic applications. Antibody-conjugated iron oxide magnetic nanoparticles were developed to allow noninvasive targeting of a specific alveolar macrophage subpopulation in the lung of a LPS-induced COPD animal model using a free-breathing UTE radial MR imaging protocol and simultaneously detect the inflammation progression.

Yun-Ming Wang¹, Shou-Cheng Wu¹, Chia-Yun Chen², Gin-Chung Liu², and Yu-Jen Chen^1
1Department of Biological Science and Technology, National Chiao Tung University, HsinChu, Taiwan, ²Department of Medical Imaging, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

In search of a unique and reliable contrast agent targeting pancreatic adenocarcinoma, new multifunctional nanoparticles (MnMEIO-silane-NH2-(MUC4)-mPEG NPs) were successfully developed in this study. Mucin4-expression levels were determined through different imaging studies in a panel of pancreatic tumor cells (HPAC, BxPC-3, and Panc-1) both in vitro and in vivo studies. The in vitro T2-weighted MR imaging study in HPAC and Panc-1 tumor cells treated with NPs showed - 89.1 ¡Ó 5.7% and - 0.9 ¡Ó 0.2% contrast enhancement whereas in in vivo study, it is found to be - 81.5 ¡Ó 4.5% versus - 19.6 ¡Ó 5.2% (post-injection) respectively.

Stephen Dodd¹, Gary Zabow^1,2, Nikorn Pothayee¹, John Moreland², and Alan Koretsky^1
1Laboratory of Functional and Molecular Imaging, NINDS, National Institutes of Health, Bethesda, MD, United States, ²Physical Measurements Division, NIST, Boulder, Colorado, United States

A demonstration of micro-fabricated gold-coated iron particles, 1 µm in diameter for an in vivo experiment is presented. These particles have a higher moment than iron-oxide based particles, and offer greater contrast for a single particle in a smaller volume. The fabrication process is briefly described, and single particle contrast is shown in phantom images. After injection into the lateral ventricle, particles were shown to track from the subventricular zone to the olfactory bulb in the rat brain, with contrast still observed after 6 weeks.

Sophie Laurent¹, Adeline Hannecart², Dimitri Stanicki², Luce Vander Elst², Sebastien Boutry³, Sebastien Lecommandoux⁴, Julie Thévenot⁴, Colin Bonduelle⁴, Aurélien Trotier⁵, Philippe Massot⁵, Sylvain Miraux⁵, Olivier Sandre⁴, and Robert N Muller^2,3
1General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, UMONS, Mons, Hainaut, Belgium, ²General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, UMONS, Hainaut, Belgium, ³Center for Microscopy and Molecular Imaging, Hainaut, Belgium, ⁴Laboratoire de Chimie des Polymères Organiques, Université de Bordeaux, France, ⁵Résonance Magnétique des Systèmes Biologiques, Université de Bordeaux, France

Jeffamine® M-2005 (PEO5-st-PPO37) was grafted onto USPIO. The resulting polymer-nanosystem exhibits a temperature-responsive colloidal behaviour, the surface reversibly changing from hydrophilic below LCST to hydrophobic above it. This phenomenon was utilized to design thermo-sensitive contrast agents for MRI. To illustrate the interest of such polymer-coated USPIO for MRI thermometry, sample tubes were imaged on low-field (8.25 MHz) and high-field (300 MHz) MRI scanners with either T1- or T2*-weighted spin echo sequences. The positive contrast on low-field MR images and the linearity of the signal with a T2*-weighted sequence over the whole temperature range 15°C– 50°C renders these polymer-USPIO interesting positive contrast agents, also working as “nano-thermometers”.

Francesca Garello¹, Cristina Chirizzi¹, Francesca Arena², Sara Figueiredo³, Daniela Delli Castelli¹, Valeria Menchise¹, Silvio Aime^1,2, and Enzo Terreno^1,2
1Molecular biotechnology and health sciences, University of Torino, Torino, Torino, Italy, ²Center for Preclinical Imaging, University of Torino, Colleretto Giacosa, Torino, Italy,³Department of Life Sciences, Faculty of Sciences and Technology, and Center for Neurosciences and Ce, University of Coimbra, Coimbra, Coimbra, Portugal

Glucan particles (GPs) could be considered innovative and biocompatible microcarriers. Their high affinity for Dectin-1 receptor, expressed on different phenotypes of immune system cells, makes them suitable for imaging inflammatory processes. In this work, GPs were efficiently loaded with either paramagnetic Gd-based compounds (for proton MRI) or perfluorocarbons (PFCs, for ¹⁹F MRI). The carriers obtained showed very high values of relaxivity and fair fluorine payloads. The limit of sensitivity related to loaded GPs was explored both by ¹H and ¹⁹F MRI. Moreover, J774.A1 macrophage incubation with loaded GPs and subsequent MRI of cells at 7 T were performed.

Gin-Chung Liu¹, Yu-Jen Chen², Chia-Yun Chen¹, Shou-Cheng Wu², and Yun-Ming Wang^2
1Department of Medical Imaging, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ²Department of Biological Science and Technology, National Chiao Tung University, HsinChu, Taiwan

In this study, we developed a MRI contrast agent ([Gd-NBCB-TTDA-Leg(L)]) and a NIR fluorescence (NIRF) probe (CyTE777-Leg(L)-CyTE807) to monitor legumain activity in tumors. The MRI contrast agent was prepared by introduction of cyclobutyl and benzyl group residues to TTDA, followed by a legumain-specific substrate peptide (Leg(L)). The NIRF probe was designed by conjugating two fluorochromes with Leg(L). Peptide cleavage of the MRI contrast agent by legumain can increase its hydrophobicity and promote contrast enhancements. Similar cleavage effect on NIR probes relieves the self quench of the probe.

Min-Kyoung Kang¹, Ki-Hye Jung², Soyeon Kim¹, Hyun-Jeong Jeong¹, Garam Choi¹, Eun-Young Jeon³, Hee-Kyung Kim¹, Tae-Jeong Kim², and Yongmin Chang*^1,4
1Department of Medical and Biological Engineering, Kyungpook National University, Daegu, Korea, ²Department of Applied Chemistry, Kyungpook National University, Daegu, Korea, ³Institute Biomedical of engineering, Kyungpook National University Hospital, Daegu, Korea, ⁴Department of Diagnostic Radiology and Molecular Medicine, Kyungpook National University Hospital, Daegu, Korea

Amino functionalized silica coated gadolinium nanoparticle (Gd@SiO₂-NH₂) based perfectly soluble potential theranostic agents formulated as Gd@SiO₂-NHCO-DO3A-BTA. The preparation initially requires the formation of Gd@SiO₂-NH₂ through self-condensation on the surface of GdNPs in DEG to react with TEOS and APTES. In order to increase solubility as well as used by theranostic agents, Gd@SiO₂-NH₂ was further conjugated with DO3A-benzothiazole to give the desired product. Gd@SiO₂-NHCO-DO3A-BTA reveals high MR relaxivity (R₁ = 8.74 mM^-1s^-1) and in vitro and in vivo monitoring provides high uptake affinity to tumor. Therefore, this system may be put into a new family of multifunctional theranostic CAs.

Sankarprasad Bhuniya¹, Jongeun Kang^1,2, and Kwan Soo Hong^3,4
1Division of Magnetic Resonance Research, Korea Basic Science Institute, Ochang Eup, Chungbook, Korea, ²Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Korea, ³Division of Magnetic Resonance Research, Korea Basic Science Institute, Ochang -Eup, Chungbook, Korea, ⁴bGraduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Korea

We have synthesized a Cu2+ triggered bimodal MRI contrast agent (1) comprising 1,8-naphthalimide as a fluorescence reporter and a diethylenetriamine tetraacetic acid (DTTA) unit as a chelator for Gd3+ ions. In the presence of Cu2+ ions, the fluorescence intensity of 1 decreased because of the paramagnetic nature of Cu2+ ions. In contrast, with the addition of Cu2+ ions, first, the total number of water molecules coordinated to 1 increased, and then the T1-weighted MR signal increased. The new bimodal contrast agent was nontoxic and able to provide bimodal, i.e., fluorescence and T1-weighted MRI imagings in the cellular medium in the presence of Cu2+ ions. This new contrast agent can be used to detect free Cu2+ ions in living cells and inspire researchers to develop new probes to detect free metal ions in vivo.

Pasquina Marzola¹, Leonardo Ghin², Stefano Tambalo³, Giamaica Conti³, Silvia Mannucci³, Alice Busato³, Elvira Fantechi⁴, Claudia Innocenti⁴, Claudio Sangregorio⁴, Alessandro Lascialfari⁵, Tomas Orlando⁵, Roberto Bassi², and Andrea Sbarbati^3
1Department of Computer Science, University of Verona, Verona, Italy, ²Department of Biotechnology, University of Verona, Verona, Italy, ³Department of Neurological and Movement Science, University of Verona, Verona, Italy, ⁴INSTM-LaMM, Dept. of Chemistry, University of Florence, Florence, Italy, ⁵Department of Physics, University of Milan, Milan, Italy

Naturally occurring iron-oxide nanoparticles, namely Magnetosomes (MS), are here proposed as theranostic agents for imaging and thermotherapy of tumors. Magnetosomes, produced by magnetotactic bacteria, are organized in chains that are used by bacteria as a compass for geomagnetic navigation. In this paper , several techniques have been used to characterize magnetic nanoparticles and we demonstrate that MS extracted from Magnetospirillum gryphiswaldence strain MSR-1 have high transversal relaxivity and high hyperthermal efficiency.

Eszter Boros¹, Shima Karimi², Nathaniel Kenton¹, Lothar Helm², and Peter Caravan^1
1Radiology, Massachusetts General Hospital/ Harvard Medical School, Charlestown, Massachusetts, United States, ²EPFL, Switzerland

Magnetic resonance imaging (MRI) at high magnetic fields benefits from an increased signal to noise ratio, however T1 based MR contrast agents show decreasing relaxivity (r1) at higher fields. For this purpose, we have successfully explored the Gd(DOTAla) complex and its derivatives. It was our aim to design new Gd(DOTAla)-like agents with a shorter water residency time (τM), higher relaxivities at high magnetic fields, and subsequently test them in vivo. A new compound, based on the phosphonate analogue DOTAlaP represents a Gd-based agent with improved properties for high field imaging compared to the currently clinically used agent gadofosveset.

Stefano Lepore¹, Karl Sydow², Susanne Drechsler¹, Min-Chi Ku¹, Helmar Waiczies^1,3, Conrad Martin¹, Irene Schuetz², Bettina Purfürst⁴, Margitta Dathe², Thoralf Niendorf^1,5, and Sonia Waiczies^1,5
1Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine, Berlin, Berlin, Germany, ²Department of Medicinal Chemistry/Chemical Biology, Leibniz-Institut für Molekulare Pharmakologie, Berlin, Berlin, Germany, ³MRI.Tools GmbH, Berlin, Berlin, Germany, ⁴Electron Microscopy, Max Delbrück Center for Molecular Medicine, Berlin, Germany, Berlin, Berlin, Germany, ⁵Experimental and Clinical Research Center (ECRC), Berlin, Berlin, Germany

Studying the migratory behavior of immune cells is pivotal to better understand the development of immune-mediated pathologies, It has been already demonstrated that fluorine (¹⁹F) MRI enables spatio-temporal tracking of dendritic cells (DC) in vivo. The aim of this study is to overcome the ¹⁹F sensitivity barriers by increasing the uptake of¹⁹F nanoparticles in DC. Therefore we explored the impact of aminophospholipids incorporated into the ¹⁹F nanoparticle on uptake by DC and on labeling. We show how this incorporation resulted in fluorine uptake increase confirmed by ¹⁹F spectroscopy and microscopy, with minor changes in the migration capability of DC.

Joshua E Goldberger¹, Arijit Ghosh², Christian Buettner², Michelle Williams³, and Michael F. Tweedle^3,4
1Chemistry and Biochemistry, The Ohio State University, Columbus, OH, United States, ²Chemistry, The Ohio State University, Columbus, OH, United States, ³Wright Center of Innovation in Biomedical Imaging, The Ohio State University, Columbus, OH, United States, ⁴Radiology, Chemistry and Biochemistry, Biophysics, The Ohio State University, Columbus, OH, United States

FDG PET targets Warburg metabolism (including low pHe) but suffers low spatial resolution-based sensitivity (~1 cm). We developed a strategy for controlling the self-assembly transitions of Gd-PA molecules in the 10 – 1000+ nm range as a function of pHe and concentration, measured the transitions in serum, and biodistributions in mice, uncovering significant differences in behavior among transitioning examples. If we can harness the power of self-assembly to trap Gd chelates in the acidic tumor environment, we should be able to image tumors at the < 1 mm spatial resolution of MRI using Warburg metabolism as the target.

Gary Zabow^1,2, Stephen Dodd¹, John Moreland², and Alan Koretsky^1
1NINDS, NIH, Bethesda, Maryland, United States, ²Physical Measurements Division, NIST, Boulder, Colorado, United States

Newly developed microfabricated multispectral MRI agents offer multispectral contrast that is tunable over broad frequency ranges allowing for the possibility of highly multiplexed imaging. However, such agents has thus far been limited by their relatively large sizes. To overcome this limitation and expand their biological utility, this work shows how it is possible to shrink these agents to sub-micron and nano size scales. The nanofabrication techniques involved, and the NMR spectral signatures that result from agents over a 100 times less massive than any previously published equivalent are presented, and future benefits and limits to further agent miniaturization are discussed.